Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
This variantScenario
BenignPathogenic
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
About NF1
NF1 encodes neurofibromin, a tumor suppressor protein that negatively regulates the RAS signal transduction pathway. As a GTPase-activating protein, it helps switch RAS proteins from their active to inactive state, keeping cell growth in check; loss of NF1 function leaves RAS overactive and drives downstream growth pathways such as MAPK/ERK and PI3K. Inherited changes in NF1 cause the cancer-predisposition syndrome neurofibromatosis type 1, and are also linked to juvenile myelomonocytic leukemia and Watson syndrome. Somatic changes in NF1 are found in many tumor types, including breast cancer, melanoma, and glioma.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen NF1 VCEP v1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
Met (stand-alone benign): highest population allele frequency 3.06% (African ancestry, gnomAD v4.1) exceeds the >1% BA1 threshold about 3-fold.
BS1Supporting
BS1 · supporting
Met (supporting): observed maximum allele frequency 3.06% exceeds the ~0.01–0.02% expected for a dominant NF1 allele by over 150-fold.
BS2Supporting
BS2 · supporting
Met (supporting): 44 homozygotes in gnomAD v4.1 general-population cohorts are incompatible with a near-fully penetrant dominant NF1 allele.
BP7Supporting
BP7 · supporting
Met (supporting): synonymous change, no predicted splice impact (SpliceAI max delta 0.009), and high population frequency indicating no strong conservation.
Recorded classification: Benign
Benign: BA1 met at stand-alone strength (max population AF 3.06% vs the >1% threshold), with concordant BS1, BS2, and BP7; no pathogenic criterion was met.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
2,658 / 1,613,546 alleles
gnomAD v4.1: 2,658 / 1,613,546 alleles. Recorded AF 0.0016473. Recorded homozygote count 44.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00278483; MAF= 0.27848%, 785/281884 alleles, homozygotes = 18) and has highest observed frequency in the African/African American population (AF= 0.0288855; MAF= 2.88855%, 720/24926 alleles, homozygotes = 18); grpmax FAF= 0.0269323.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0023894862604540022, 44/18414 alleles, homozygotes = 0).
ACMG/AMP criteria under ClinGen NF1 VCEP v1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 10 not met · 5 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Governing framework: the ClinGen NF1/Schwannomatosis VCEP CSPEC v1.0 (doc 1553923915) is registered for NF1 but its ruleset payload is empty (framework_complete=false), so no gene-specific PS2/PM6/PP1/BS4 specifications were retrievable; generic ACMG/AMP 2015 (PMID:25741868) was used for this group.
The case-evidence bundle contains no proband, parental, or family data of any kind: exhaustive scans for de novo, segregation, maternal, paternal, meiosis, proband, parent, family, pedigree, and inheritance content returned zero matches across review_manifest, case_summary, source_registry, prefetch, evidence, literature_pass, vcep_materials, and fulltext_map.
Consequently PS2 (confirmed de novo), PM6 (assumed de novo), PP1 (co-segregation in affected family members), and BS4 (lack of segregation in affected family members) are all returned as not_assessed; the sole gap for each is the total absence of family-based evidence for c.2022C>T.
Context noted but not used for these criteria: ClinVar (VCV000141819) classifies the variant Benign/Likely benign across 18 laboratory submissions, and gnomAD v4.1 shows a high population frequency (total AF 0.1647%; AFR AF 3.06%; 44 homozygotes). Population frequency supports benign-side frequency criteria handled by other groups and does not substitute for BS4 non-segregation evidence.
No publication in the bundle mentions this variant, so no publication-based de novo or segregation evidence exists for PS2/PM6/PP1/BS4.
Functional group: neither PS3 nor BS3 is met because the record contains no well-established functional study of NF1 c.2022C>T (p.Ser674=). PS3 lacks any evidence of a deleterious effect; BS3 lacks functional evidence of no damaging effect (in silico SpliceAI prediction and ClinVar laboratory classifications do not meet the BS3 evidentiary bar).
The governing NF1 CSPEC v1.0 could not supply PS3/BS3-specific calibration because its rule payload is empty in this case (framework_complete=false), so generic ACMG/AMP 2015 (PMID:25741868) definitions were applied; this is noted as a gap for human retrieval of the specification text.
Framework: the ClinGen Neurofibromatosis and Schwannomatosis Expert Panel specification for NF1 v1.0 (CSPEC doc 1553923915, precedence rank 1) was found, but its ruleset payload is empty (framework_complete: false, rule_payload: {}, criteria list empty) and no local gene-framework files exist, so generic ACMG/AMP 2015 (PMID 25741868) governs this group's criteria.
Variant context: NM_001042492.2:c.2022C>T (p.Ser674=) is a synonymous NF1 variant with substantial population frequency (gnomAD v2.1 overall AF 0.278%, AFR AF 2.889%, 18 homozygotes; gnomAD v4.1 overall AF 0.165%, AFR AF 3.06%, 44 homozygotes) and an 18-laboratory ClinVar Benign/Likely benign consensus (2-star) with zero expert-panel input.
PS4 is not met: no case-control or NF1 case-cohort enrichment data exist for this variant, and its high population frequency is incompatible with pathogenic enrichment.
PP4 is not met: no case-level phenotype data link this variant to the NF1 phenotype; screened NF1 clinical documents (PMID 17636453, 25394175, 32602153) describe NF1 diagnostic criteria but never mention c.2022C>T.
PP5 and BP6 are not met: per the governing rule, both are restricted to exact-variant ClinVar expert-panel classifications, and VCV000141819 has zero expert-panel submissions; the aggregate 2-star Benign/Likely benign label from ordinary clinical laboratories must never trigger either criterion.
BP5 is not met: no proband-level evidence of an alternate molecular basis of disease in carriers of this variant exists in ClinVar or the literature.
No criterion in this group is met; the benign-laboratory consensus and population data relevant to this variant are accounted for by criteria outside this group (e.g., population-frequency and other benign criteria).
Allelic group: PM3 is not applicable — neurofibromatosis type 1 (NF1) is autosomal dominant per the CSPEC NF1 v1.0 ruleset metadata, and generic ACMG/AMP PM3 (PMID:25741868) requires a recessive disorder context.
Allelic group: BP2 is not assessed — no phase/co-occurrence data (variant observed in cis or in trans with a pathogenic NF1 variant) exists in ClinVar, gnomAD, or the literature for this case; the data gap is documented.
The NF1 VCEP rule payload was empty in this case bundle (framework_complete: false); generic ACMG/AMP 2015 definitions (PMID:25741868) were used for both allelic criteria.
Governing framework: the ClinGen Neurofibromatosis and Schwannomatosis Expert Panel (NF1 VCEP) specification v1.0 (cspec) was identified, but its PP3/BP4/BP7 rule content was not retrievable in machine-readable form in this case (criteria list empty, rule_payload {}), and no gene-specific PP3/BP4 lookup spreadsheet or other VCEP supporting material is present in vcep_materials. Generic ACMG/AMP 2015 (PMID 25741868) with the lab's generic in-silico calibration (generic_acmg_combination_rules) therefore governs these criteria.
Variant type: synonymous (NM_001042492.2:c.2022C>T, p.(Ser674=)). The splice-impact path (SpliceAI) is the applicable computational-evidence path; the missense path (REVEL/BayesDel/aGVGD) does not apply to a synonymous variant.
PP3 not met: SpliceAI max delta 0.009 predicts no splice impact; no missense-path score applies or is available; no computational evidence supports a deleterious effect.
BP4 not met: only a single computational no-impact line exists (SpliceAI), which is applied under BP7; the same prediction is not double-counted across BP4 and BP7.
BP7 met (supporting): synonymous variant with no predicted splice impact (SpliceAI max delta 0.009) and a nucleotide that is not highly conserved (high gnomAD frequencies with multiple homozygotes).
Population evidence for NF1 c.2022C>T (p.Ser674=) is strongly benign: BA1 met (stand-alone), BS1 met (supporting), BS2 met (supporting), PM2 not met.
The variant is a synonymous change (gnomAD-Canada VEP: synonymous_variant) present at overall AF 0.1647% (gnomAD v4.1) / 0.2785% (gnomAD v2.1) and African/African American AF 3.06% / 2.89%, with 44 / 18 homozygotes in the two releases.
For autosomal dominant NF1 (prevalence ~1/3000, near-complete penetrance), the expected pathogenic-allele frequency is ~0.01-0.02%; the observed maximum AF (3.06%) exceeds this by >150-fold and even the overall AF exceeds it ~10-fold.
The elevated frequency is replicated across three independent datasets (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0) with HWE-consistent homozygosity, supporting a genuine benign population polymorphism rather than a technical artifact.
ClinVar (2-star, 16 laboratories Benign; clinvar) is consistent with these population conclusions but was not used as the basis for any population criterion.
Framework: ClinGen NF1 CSPEC v1.0 (cspec) was identified as the governing VCEP but its rule payload was empty in this bundle; generic ACMG/AMP 2015 (PMID:25741868) was applied with the LYFESCI/HERA v7 non-VCEP gnomAD thresholds (BA1 max AF >1%, BS1 >0.3%, PM2 <0.1%).
No criteria match.
Met · 4
BA1Stand aloneMet (stand-alone benign): highest population allele frequency 3.06% (African ancestry, gnomAD v4.1) exceeds the >1% BA1 threshold about 3-fold.
Details ▾Hide ▴
Reasoning
BA1 is met at stand-alone strength. gnomAD v4.1 (gnomad_v4) shows the highest observed population AF in African/African American individuals at 3.06% (2,292/74,908 alleles; grpmax FAF 0.0296), and gnomAD v2.1 (gnomad_v2) independently confirms an AFR AF of 2.89% (720/24,926 alleles; grpmax FAF 0.0269); both exceed the applied non-VCEP BA1 threshold of max population AF >1% by roughly 3-fold. gnomAD-Canada v1.0 (gnomad_canada, overall AF 0.239%, 44/18,414 alleles) corroborates that this is a common population polymorphism in an independent general-population cohort. A pathogenic NF1 allele at ~3% frequency in any ancestry is incompatible with NF1 (autosomal dominant, population prevalence ~1/3000, near-complete penetrance). The gnomAD-Canada raw record flags the locus as a segmental duplication (segdup=true); this artifact concern was evaluated and deemed unlikely to explain the frequency because the AF is replicated across three independent datasets and the homozygote counts are HWE-compatible at the AFR AF (observed 43/37,454 AFR individuals = 0.115% vs expected ~0.094%). Caveat documented in warnings: under the literal ACMG/AMP 2015 BA1 bar (AF >5%), BA1 would not be met, but BS1 would still clearly be met, so the benign conclusion does not hinge on this threshold choice. Governing framework: NF1 CSPEC v1.0 identified but rule payload empty in this bundle, so generic ACMG/AMP 2015 (PMID:25741868) applies.
Applied non-VCEP gnomAD thresholds per LYFESCI/HERA v7 policy (BA1 max population AF >1%) because the NF1 CSPEC v1.0 rule payload was not available in this case bundle.
gnomAD v4.1 (gnomad_v4): overall AF 0.1647% (2,658/1,613,546 alleles); highest population AF in African/African American at 3.06% (2,292/74,908 alleles); grpmax FAF 0.0296.
gnomAD v2.1 (gnomad_v2): overall AF 0.2785% (785/281,884 alleles); highest population AF in African/African American at 2.89% (720/24,926 alleles); grpmax FAF 0.0269.
gnomAD-Canada v1.0 (gnomad_canada): AF 0.239% (44/18,414 alleles), 0 homozygotes; independent general-population corroboration of an elevated frequency.
BA1 stand-alone reasoning: NF1 is autosomal dominant with population prevalence ~1/3000; an allele at 3.06% in Africans is orders of magnitude above any credible pathogenic-allele frequency for this disorder.
Artifact evaluation: cross-dataset AF replication (v2.1, v4.1, gnomAD-Canada) and HWE-consistent homozygosity argue against a paralogous-mapping artifact despite the segdup=true flag on the gnomAD-Canada raw record.
Still missing
NF1 CSPEC v1.0 (cspec doc 1553923915) rule payload was empty in this case; an NF1-specific BA1 calibration could not be retrieved and would need human retrieval of the specification text.
gnomAD v4 variant-page QC/region flags (e.g., in_segdup) were not present in this bundle; the gnomAD-Canada segdup=true flag was evaluated as unlikely to explain the frequency, but a direct check of gnomAD v4 QC flags would fully close this artifact question.
BS1SupportingMet (supporting): observed maximum allele frequency 3.06% exceeds the ~0.01–0.02% expected for a dominant NF1 allele by over 150-fold.
Details ▾Hide ▴
Reasoning
BS1 is met (supporting). The ACMG/AMP 2015 definition (PMID:25741868) is that the allele frequency is greater than expected for the disorder. For autosomal dominant NF1 with population prevalence ~1/3000 and near-complete penetrance, the expected pathogenic-allele frequency is on the order of 0.01-0.02%; the observed maximum population AF (3.06% in AFR, gnomAD v4.1; 2.89% gnomAD v2.1) exceeds this by >150-fold, and even the overall AF (0.1647% v4.1; 0.2785% v2.1) exceeds it by ~10-fold. The max-AF values cross the applied non-VCEP BS1 threshold (>0.3%) roughly 10-fold. gnomAD-Canada (0.239% overall in an unselected Canadian general-population cohort) independently corroborates an elevated frequency.
Applied non-VCEP gnomAD threshold BS1 >0.3% (max population AF) per LYFESCI/HERA v7 policy; NF1 CSPEC v1.0 rule payload unavailable in this bundle.
gnomAD v4.1: AFR AF 3.06%; gnomAD v2.1: AFR AF 2.89% — both >0.3% threshold by ~10-fold.
Expected pathogenic-allele frequency for AD NF1 (prevalence ~1/3000, near-complete penetrance) is ~0.01-0.02%; observed overall AF 0.1647% (v4.1) is ~10x higher and observed max AF 3.06% is >150x higher (BS1 'allele frequency greater than expected for disorder', PMID:25741868).
gnomAD-Canada v1.0 overall AF 0.239% in an independent general-population cohort corroborates the elevated frequency.
Still missing
NF1 prevalence (~1/3000) and penetrance used in the 'greater than expected for the disorder' reasoning are general clinical knowledge and are not sourced within this case bundle; the fixed non-VCEP BS1 threshold (>0.3% max AF) is decisive independently of these figures.
BS2SupportingMet (supporting): 44 homozygotes in gnomAD v4.1 general-population cohorts are incompatible with a near-fully penetrant dominant NF1 allele.
Details ▾Hide ▴
Reasoning
BS2 is met (supporting). gnomAD v4.1 (gnomad_v4) reports 44 homozygous individuals (43 in African/African American) and gnomAD v2.1 (gnomad_v2) reports 18 homozygotes for this variant in general-population cohorts. NF1 is autosomal dominant with near-complete penetrance, with characteristic features manifesting in childhood; dozens of homozygous adults in unselected population cohorts is incompatible with a pathogenic NF1 allele (biallelic NF1 inactivation is a severe, rare phenotype). Caveat: gnomAD is not a phenotype-screened healthy cohort, so BS2 here rests on homozygous general-population presence rather than confirmed unaffected adult status; the magnitude of the observation (44 homozygotes at v4.1) is decisive for this analysis.
gnomAD v4.1 (gnomad_v4): 44 homozygotes total, 43 in African/African American (74908 AFR alleles), consistent with Hardy-Weinberg expectation at AFR AF 3% (observed 43/37,454 AFR individuals = 0.115% vs expected q^2 ~0.094%).
gnomAD v2.1 (gnomad_v2): 18 homozygotes total (all in African/African American).
BS2 (ACMG/AMP 2015, PMID:25741868): observed in a healthy adult individual for an autosomal dominant disorder; for a near-fully-penetrant AD disorder like NF1, homozygous presence in general-population cohorts is strong evidence against pathogenicity.
gnomAD v4/v2 cohorts are not phenotype-screened for NF1; per-individual confirmed-unaffected adult status is unavailable, so BS2 relies on homozygous general-population presence (44 homozygotes, v4.1) rather than documented health.
NF1 CSPEC v1.0 (cspec doc 1553923915) rule payload was empty in this case; an NF1-specific BS2 calibration could not be retrieved.
BP7SupportingMet (supporting): synonymous change, no predicted splice impact (SpliceAI max delta 0.009), and high population frequency indicating no strong conservation.
Details ▾Hide ▴
Reasoning
All three BP7 components are satisfied. (1) Synonymous variant: Mutalyzer normalization confirms NM_001042492.2:c.2022C>T is synonymous, NP_001035957.1:p.(Ser674=). (2) Splicing prediction algorithms do not predict impact to the splice consensus sequence nor creation of a new splice site: SpliceAI max delta = 0.009 (DS_AG 0.009, DS_AL 0.002, DS_DG 0.000, DS_DL 0.002), below the 0.2 recommended cutoff of the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751) and below the 0.1 threshold of the lab generic calibration; the variant is in the exon body (~22 nt from the exon's 5' end), not at a canonical splice position, and predicted cryptic splice gains are distant and negligible (DP_DG 370, DP_DL 229). (3) Nucleotide not highly conserved: the variant is a common polymorphism with high allele frequency and multiple homozygotes (gnomAD v4.1 AF 0.165% overall, 44 homozygotes, AFR AF 3.06% with 43 homozygotes; gnomAD v2.1 AF 0.278%, 18 homozygotes; gnomAD-Canada AF 0.239%), indicating the position is not under strong purifying selection.
Rule
Generic ACMG/AMP 2015 BP7 (Richards et al., PMID 25741868): a synonymous (silent) variant for which splicing prediction algorithms do not predict impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Default strength: supporting.
Evidence considered
Synonymous status: Mutalyzer normalization (prefetch) confirms NM_001042492.2:c.2022C>T is a synonymous variant, NP_001035957.1:p.(Ser674=).
SpliceAI (spliceai) max delta score 0.009 - no impact predicted on the splice consensus sequence and no new splice site (DS_AG 0.009 acceptor gain, DS_DG 0.000 donor gain, DS_DL 0.002, DS_AL 0.002); this is below the 0.2 cutoff recommended in the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751) and below the 0.1 threshold of the lab generic calibration (generic_acmg_combination_rules).
The variant is in the exon body (transcript-relative g.2406; exon spans c.2001-2250), about 22 nt from the exon's 5' end and not within any canonical splice consensus sequence; SpliceAI predicted splice-gain events are distant (DP_DG 370, DP_DL 229) with negligible delta scores.
Nucleotide not highly conserved: gnomAD v4.1 (gnomad_v4) total AF 0.0016473 (2658/1613546 alleles, 44 homozygotes) with African/African American AF 0.0305975 (2292/74908 alleles, 43 homozygotes); gnomAD v2.1 (gnomad_v2) total AF 0.00278483 (785/281884 alleles, 18 homozygotes); gnomAD-Canada (gnomad_canada) AF 0.002389 (44/18414 alleles). A nucleotide position carrying a variant at these frequencies with multiple homozygotes is not under strong purifying selection, i.e., not highly conserved.
Still missing
No direct conservation score (e.g., phyloP/GERP) was present in the case bundle; the 'nucleotide not highly conserved' component of BP7 is supported by the variant's high population frequency with multiple homozygotes in gnomAD rather than a direct conservation metric.
PS3Not met: no functional study of this variant exists — no assay of neurofibromin activity, splicing, or RAS pathway function was found.
Details ▾Hide ▴
Reasoning
PS3 (generic ACMG/AMP 2015, PMID:25741868) requires well-established functional studies demonstrating a deleterious effect. No functional study of NF1 c.2022C>T (p.Ser674=) exists anywhere in the case evidence bundle: no variant-specific assay (neurofibromin GTPase-activating protein activity, RAS/MAPK pathway readouts, mRNA/cDNA or minigene splicing analysis) was identified in evidence.json, literature_pass.json, or the retrieved publications. The only 'functional'-themed papers retrieved (PMID:24033266, PMID:25741868, PMID:26467025) are methodology/guideline papers that do not test this variant. OncoKB lists the variant as 'Unknown Oncogenic Effect' with no variant-specific citations, and COSMIC reports a single somatic occurrence (COSV104420496, n=1), which is an observation count, not functional assay evidence. The governing NF1 CSPEC v1.0 (cspec) was located but its rule payload was empty (framework_mode=unstructured_ruleset, framework_complete=false), so no NF1-specific PS3 calibration was retrievable and the generic definition applies. PS3 is therefore not met.
Governing framework: ClinGen Neurofibromatosis and Schwannomatosis EP NF1 CSPEC v1.0 (cspec) is the applicable gene-specific specification, but its structured rule payload is empty/unstructured in this case (framework_mode=unstructured_ruleset, framework_complete=false); no NF1-specific PS3 wording was retrievable, so generic ACMG/AMP 2015 definitions (PMID:25741868) were applied.
No well-established functional study of NF1 c.2022C>T (p.Ser674=) was identified in the case evidence bundle or literature pass; no variant-specific assay (neurofibromin GAP activity, RAS/MAPK readouts, mRNA/cDNA or minigene splicing assay) is present in the record.
The 'functional'-themed publications retrieved (PMID:24033266, PMID:25741868, PMID:26467025) are methodology/guideline papers; none report functional testing of this variant.
OncoKB (oncokb) lists NF1 c.2022C>T as 'Unknown Oncogenic Effect' with no variant-specific functional citations (is_variant_specific=false).
COSMIC (cosmic) reports a single somatic occurrence (COSV104420496, n=1); a somatic observation count is not functional assay evidence and was not used for PS3.
Still missing
No variant-specific functional assay of NF1 c.2022C>T (p.Ser674=) was identified; PS3 cannot be met without well-established functional studies demonstrating a deleterious effect.
NF1 CSPEC v1.0 (cspec doc 1553923915) rule payload was empty in this case; an NF1-specific PS3 calibration could not be retrieved and would need human retrieval of the specification text.
PS4Not met: no case-control or NF1 case-cohort study shows enrichment; ClinVar carries only routine laboratory Benign classifications.
Details ▾Hide ▴
Reasoning
PS4 (case-control enrichment) requires the prevalence of the variant in affected individuals to be significantly increased compared with controls. No case-control or NF1 case-cohort study of NM_001042492.2:c.2022C>T (p.Ser674=) exists in the evidence bundle: ClinVar VCV000141819 carries no validated PMIDs and no criterion leads (validated_pmids=0, criterion_lead_submissions=0), and all 18-19 submissions are ordinary clinical-laboratory Benign (16), benign (1), and Likely benign (1) classifications with no case series. COSMIC lists a single somatic occurrence (COSV104420496, n=1), which is somatic, not germline case-control enrichment evidence. Population frequency is high for an NF1 variant (gnomAD v2.1 overall AF 0.278%, AFR AF 2.889% with 18 homozygotes; gnomAD v4.1 overall AF 0.165%, AFR AF 3.06% with 44 homozygotes), which is incompatible with pathogenic enrichment of this synonymous variant in NF1 cases. PS4 is not met. Framework note: the NF1 ClinGen/Schwannomatosis CSPEC (doc 1553923915, v1.0) was retrieved with an empty ruleset (framework_complete=false, rule_payload={}, criteria list empty), so generic ACMG/AMP 2015 (PMID 25741868) governs; no VCEP-specific PS4 specification was available.
Rule
PS4: The prevalence of the variant in affected individuals is significantly increased compared with controls (PMID:25741868, Table 3; no VCEP-specific PS4 rule retrievable - NF1 CSPEC ruleset empty)
Evidence considered
ACMG/AMP 2015 (PMID 25741868, Table 3) defines PS4 (strong) as 'The prevalence of the variant in affected individuals is significantly increased compared with controls', typically requiring a statistically significant case-control comparison.
ClinVar variation 141819 submission audit: 20 submissions, 16 usable for classification, 0 usable for criterion leads, 0 expert-panel submissions, 0 validated PMIDs, 4 rejected PMIDs; all submitters are clinical laboratories (single-submitter SCVs) classifying Benign/Likely benign, providing no case-series or enrichment data.
gnomAD v2.1: overall AF 0.278% (785/281884 alleles), 18 homozygotes; AFR subpopulation AF 2.889% (720/24926 alleles), 18 homozygotes; grpmax FAF 2.69% - a common variant, inconsistent with a pathogenic NF1 allele enriched in affected individuals.
gnomAD v4.1: overall AF 0.165% (2658/1613546 alleles), 44 homozygotes; AFR subpopulation AF 3.06% (2292/74908 alleles), 43 homozygotes; grpmax FAF 2.96% - corroborates high population frequency in the same direction.
COSMIC record COSV104420496 documents one somatic occurrence of NF1 c.2022C>T; a somatic cancer occurrence is not germline case-control enrichment and was not used to support PS4.
Candidate case-observation papers triaged for PS4 (PMID 17636453, 25394175, 32602153) are general NF1 clinical/counseling guidance documents that do not mention c.2022C>T; they provide no case-level data for this variant (see paper_findings, variant_mentioned=false).
Still missing
No case-control or NF1 case-cohort study of this exact variant (c.2022C>T / p.Ser674=) was identified; should one become available with significant enrichment, PS4 would need re-evaluation.
PM2Not met: present at 0.16% overall and 3.06% in African ancestry in gnomAD, far above the <0.1% rarity threshold.
Details ▾Hide ▴
Reasoning
PM2 is not met. PM2 requires absence or ultra-low frequency in population databases (applied non-VCEP threshold: AF <0.1%); this variant is present at 0.1647% overall in gnomAD v4.1 (2,658/1,613,546 alleles), 0.2785% overall in gnomAD v2.1 (785/281,884 alleles), and 0.239% in gnomAD-Canada v1.0 (44/18,414 alleles), with a maximum population AF of 3.06% (AFR, v4.1). The variant is a common polymorphism, not absent or ultra-rare, so PM2 does not apply.
gnomAD v4.1 (gnomad_v4): present at overall AF 0.1647% (2,658/1,613,546 alleles) — above the 0.1% rarity threshold.
gnomAD v2.1 (gnomad_v2): present at overall AF 0.2785% (785/281,884 alleles).
gnomAD-Canada v1.0 (gnomad_canada): present at AF 0.239% (44/18,414 alleles).
PM2 (ACMG/AMP 2015, PMID:25741868): absent or at extremely low frequency in population databases; the variant is common across all queried cohorts, so PM2 is not met.
Still missing
None — the variant frequency (0.16% overall v4.1) far exceeds the 0.1% rarity threshold; the criterion is clearly not met.
PP3Not met: SpliceAI max delta 0.009 is far below the 0.2 cutoff for predicted splice impact.
Details ▾Hide ▴
Reasoning
No computational evidence supports a deleterious effect. On the splice-impact path (the applicable path for this synonymous variant), SpliceAI predicts no significant splice impact: max delta score = 0.009 (DS_AG 0.009, DS_AL 0.002, DS_DG 0.000, DS_DL 0.002), more than 20-fold below the 0.2 cutoff recommended in the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751) and below the >0.2 threshold that the lab generic calibration assigns PP3 for non-missense variants. The missense in-silico path does not apply: the variant is synonymous p.(Ser674=) (Mutalyzer normalization); REVEL returned no score (found: false; REVEL covers missense substitutions only), BayesDel has no verified published threshold and is unusable for PP3/BP4 per the generic calibration, and aGVGD is not present in this case. PP3 not met.
Rule
Generic ACMG/AMP 2015 PP3 (Richards et al., PMID 25741868) with lab generic in-silico calibration: PP3 met only if computational evidence supports a deleterious effect (SpliceAI max delta > 0.2 for synonymous/non-missense variants; REVEL > 0.750 for missense).
Evidence considered
SpliceAI lookup (spliceai) for NM_001042492.2:c.2022C>T returned max delta score = 0.009 with all four delta scores far below impact thresholds (DS_AG 0.009, DS_AL 0.002, DS_DG 0.000, DS_DL 0.002).
The SpliceAI publication (Jaganathan et al. 2019, PMID 30661751) recommends a delta-score cutoff of 0.2 for high sensitivity; the observed max delta of 0.009 is >20-fold below this, so no splice impact is predicted.
Lab generic calibration (generic_acmg_combination_rules) assigns PP3 for synonymous/non-missense variants only when SpliceAI max delta > 0.2; 0.009 does not meet this.
REVEL lookup for chr17-31226455-C-T returned no score (found: false), expected for a synonymous variant because REVEL is a missense-prediction resource.
BayesDel is not usable for PP3/BP4: no verified published threshold is available to this pipeline (generic_acmg_combination_rules); aGVGD data is not present in this case bundle.
Still missing
Missense in-silico path (REVEL/BayesDel/aGVGD) is not applicable to this synonymous variant and none produced a score; the splice-impact path is fully covered by SpliceAI.
PP4Not met: no proband with a documented NF1 phenotype carrying this exact variant is reported.
Details ▾Hide ▴
Reasoning
PP4 (phenotype specificity) requires the variant to be observed in patients whose phenotype or family history is highly specific for a disease with a single genetic etiology. Although the NF1 phenotype (cafe-au-lait macules, neurofibromas, etc.) is distinctive, no case-level phenotype data are associated with this variant: the ClinVar submissions for VCV000141819 list 'not specified'/'not provided' conditions (aggregate condition terms such as 'Neurofibromatosis, type 1' reflect submission assertions, not documented variant-phenotype observations), and none of the screened NF1 clinical documents (PMID 17636453, 25394175, 32602153) mentions c.2022C>T. No proband with a documented NF1 phenotype carrying this exact variant is reported anywhere in the bundle. PP4 is not met. Framework note: generic ACMG/AMP 2015 (PMID 25741868) governs because the NF1 CSPEC ruleset was empty.
Rule
PP4: Phenotype or family history is highly specific for a disease with a single genetic etiology (PMID:25741868, Table 3; no VCEP-specific PP4 rule retrievable - NF1 CSPEC ruleset empty)
Evidence considered
ACMG/AMP 2015 (PMID 25741868, Table 3) defines PP4 (supporting) as 'Phenotype or family history is highly specific for a disease with a single genetic etiology'.
ClinVar VCV000141819 API conditions include NF1-related terms ('Neurofibromatosis, type 1', 'Cafe-au-lait macules with pulmonary stenosis', etc.), but these are lab-asserted indication labels; individual submissions predominantly list 'not specified'/'not provided', and none documents a clinical phenotype for a carrier of this variant.
NF1 clinical documents screened for phenotype evidence (PMID 17636453, 25394175, 32602153) describe NF1 diagnostic criteria and referral indications but never mention c.2022C>T (searched c.2022C>T, p.Ser674=, S674, g.29553473); they establish the NF1 phenotype is clinically recognizable but provide no variant-phenotype link.
The NF1 VCEP rule payload was empty in this case bundle (framework_complete: false), so no VCEP-specific PP4 rule was retrievable; the generic PP4 definition was applied.
Still missing
No published case reports, case series, or ClinVar submission documenting this variant (c.2022C>T / p.Ser674=) in an individual meeting NF1 diagnostic criteria; variant-phenotype data would be required to revisit PP4.
PP5Not met: no ClinVar expert panel has classified this variant as pathogenic (zero expert-panel submissions).
Details ▾Hide ▴
Reasoning
PP5 is applied only when an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic exists. ClinVar VCV000141819 (NM_001042492.3(NF1):c.2022C>T p.Ser674=) has zero expert-panel submissions (expert_panel_submissions=0; expert_panels={}); the aggregate label is Benign/Likely benign at 2-star review status ('criteria provided, multiple submitters, no conflicts') from 18 ordinary clinical laboratories. No expert panel has classified this variant as pathogenic or likely pathogenic, and the governing rule for this pipeline states that ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger PP5. PP5 is not met.
Rule
PP5: Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation (PMID:25741868, Table 3) - operationalized here as requiring an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification
Evidence considered
ACMG/AMP 2015 (PMID 25741868, Table 3) defines PP5 (supporting) as 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation'; per the governing rule for this group, only an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic qualifies as a reputable-source assertion for PP5.
ClinVar variation 141819 submission audit: expert_panel_submissions = 0; API expert_panels = {}; review status 'criteria provided, multiple submitters, no conflicts' (2 stars) reflects 18 ordinary clinical-laboratory submitters (16 Benign, 1 benign, 1 Likely benign), none of which is an expert panel.
The aggregate ClinVar Benign/Likely benign label is an aggregate of laboratory submissions and, per the governing rule, cannot support PP5 (which requires a pathogenic assertion).
The NF1 CSPEC ruleset was empty in this case bundle, so no VCEP-specific PP5 handling was retrievable; the expert-panel-only restriction was applied.
Still missing
No ClinGen expert panel (or other ClinGen-endorsed expert panel) has classified this exact variant; PP5 would only become applicable if an expert panel issued a Pathogenic/Likely pathogenic classification for c.2022C>T.
BS3Not met: no well-established functional study demonstrates absence of damaging effect; the SpliceAI prediction is in silico only.
Details ▾Hide ▴
Reasoning
BS3 (generic ACMG/AMP 2015, PMID:25741868) requires well-established functional studies demonstrating NO damaging effect. No such study exists for NF1 c.2022C>T (p.Ser674=): there is no mRNA/cDNA analysis, minigene splicing assay, or neurofibromin functional assay in the record. The only splice-relevant data point is SpliceAI (spliceai), which predicts no significant splice impact (max delta score 0.01; DS_AG 0.009) — an in silico prediction that per ACMG/AMP 2015 does not qualify as a well-established functional study and therefore cannot satisfy BS3. The ClinVar Benign classification (clinvar, 16 laboratories) reflects aggregated laboratory classification, not functional assay evidence, and was not used to meet BS3. Because the applicable NF1 CSPEC v1.0 rule payload is empty (framework_complete=false), the generic ACMG/AMP 2015 definition governs. BS3 is therefore not met; absence of demonstrated damage is not equivalent to demonstrated absence of damage.
Governing framework: ClinGen Neurofibromatosis and Schwannomatosis EP NF1 CSPEC v1.0 (cspec) located but rule payload empty/unstructured (framework_mode=unstructured_ruleset, framework_complete=false); generic ACMG/AMP 2015 definitions (PMID:25741868) applied.
SpliceAI (spliceai) predicts no significant splice impact for c.2022C>T (max delta score 0.01, DS_AG 0.009, variant consequence 'sequence_variant'); this is an in silico prediction and was considered but rejected as insufficient for BS3, which requires well-established functional studies.
ClinVar (clinvar) classifies the variant Benign/Likely benign (2-star, 16 clinical laboratories Benign); this is aggregated classification evidence handled by other criterion groups and is not functional assay evidence for BS3.
For a synonymous variant, the ACMG/AMP 2015 functional-studies guidance (PMID:25741868) identifies mRNA-level assays (direct RNA/cDNA analysis, in vitro minigene splicing assays) as the appropriate BS3-grade evidence; none are available for this variant.
Population frequency (gnomAD v2/v4: common in African/African American, homozygotes present) is population evidence adjudicated by the frequency group, not functional evidence, and was not used for BS3.
Still missing
No mRNA-level splicing assay (RNA/cDNA analysis or in vitro minigene assay) or neurofibromin functional assay has been performed for this synonymous variant; such BS3-grade evidence would be required to meet BS3.
NF1 CSPEC v1.0 (cspec doc 1553923915) rule payload was empty in this case; an NF1-specific BS3 calibration could not be retrieved and would need human retrieval of the specification text.
BP4Not met: the only computational no-impact line (SpliceAI) is already counted under BP7 and cannot be double-counted here.
Details ▾Hide ▴
Reasoning
BP4 requires multiple lines of computational evidence suggesting no impact on the gene/gene product. The only available computational no-impact line is SpliceAI (max delta 0.009, below the 0.1 threshold of the generic calibration and the 0.2 cutoff of the SpliceAI publication). That same single prediction is the splice-impact basis of BP7 for this synonymous variant, and the same prediction must not be double-counted across BP4 and BP7. No independent second line exists: REVEL is not applicable to synonymous variants (lookup found: false), BayesDel has no verified threshold, and aGVGD is unavailable. BP4 therefore not met; the benign computational evidence is captured under BP7.
Rule
Generic ACMG/AMP 2015 BP4 (Richards et al., PMID 25741868): multiple lines of computational evidence suggest no impact on gene/gene product; lab generic calibration: SpliceAI max delta < 0.1 for non-missense variants. Not double-counted with BP7 for the same prediction.
Evidence considered
SpliceAI max delta 0.009 for c.2022C>T is below the generic calibration BP4 threshold of 0.1 (generic_acmg_combination_rules) and below the 0.2 cutoff of the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751), i.e., exactly one line of no-impact computational evidence.
Applying the same SpliceAI no-impact prediction to both BP4 and BP7 would double-count a single prediction across two criteria; per this group's adjudication rule the prediction is applied under BP7 (the variant-type-specific criterion for synonymous variants), and BP4 is not independently met.
REVEL returned no score (found: false) for this synonymous variant and cannot contribute a second line; BayesDel is uncalibrated (generic_acmg_combination_rules) and aGVGD is not present in this case.
Still missing
No second, independent line of computational no-impact evidence is available for this synonymous variant (REVEL/BayesDel/aGVGD not applicable or uncalibrated); only SpliceAI qualifies, and it is applied under BP7 without double-counting.
BP5Not met: no proband-level evidence of an alternate genetic cause of disease is reported.
Details ▾Hide ▴
Reasoning
BP5 (supporting benign) requires the variant to be found in a case with an alternate molecular basis for the disease, i.e., proband-level evidence of another genetic cause. No proband-level data exist for this variant in the evidence bundle: no co-occurrence or alternate-gene diagnosis is reported in any ClinVar submission for VCV000141819 (all submissions are aggregate Benign/Likely benign classifications with no criterion leads), and no literature reporting c.2022C>T was identified. There is therefore no evidence of an alternate molecular basis of disease to support BP5. BP5 is not met. Framework note: generic ACMG/AMP 2015 (PMID 25741868) governs because the NF1 CSPEC ruleset was empty.
Rule
BP5: Variant found in a case with an alternate molecular basis for disease (PMID:25741868, Table 5; no VCEP-specific BP5 rule retrievable - NF1 CSPEC ruleset empty)
Evidence considered
ACMG/AMP 2015 (PMID 25741868, Table 5) defines BP5 (supporting) as 'Variant found in a case with an alternate molecular basis for disease'.
ClinVar variation 141819 was reviewed for alternate-cause/co-occurrence evidence: 16 Benign, 1 benign, and 1 Likely benign clinical-laboratory submissions, no expert-panel submissions, usable_for_criterion_leads = 0, and no submission reports an alternate molecular diagnosis in a carrier.
No publication reporting this exact variant with proband-level alternate-cause information was identified in the literature pass or publication corpus.
The NF1 VCEP rule payload was empty in this case bundle (framework_complete: false), so no VCEP-specific BP5 rule was retrievable; the generic BP5 definition was applied.
Still missing
No case-level data: the variant has not been observed in any proband with a documented alternate molecular basis for disease; co-occurrence/alternate-cause evidence would be required to apply BP5.
BP6Not met: no expert panel has classified this variant as benign; routine laboratory consensus does not trigger BP6.
Details ▾Hide ▴
Reasoning
BP6 is applied only when an exact-variant ClinVar expert-panel classification of Benign/Likely benign exists. Although VCV000141819 is aggregated as Benign/Likely benign (2-star, 'criteria provided, multiple submitters, no conflicts') from 16 Benign, 1 benign, and 1 Likely benign clinical-laboratory submissions, all of these are ordinary laboratory submissions - expert_panel_submissions = 0 and expert_panels = {}. Per the governing rule for this group, ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger BP6. BP6 is not met despite the laboratory consensus, which is instead appropriately reflected by population-frequency and other benign criteria outside this group.
Rule
BP6: Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation (PMID:25741868, Table 5) - operationalized here as requiring an exact-variant ClinVar expert-panel Benign/Likely benign classification
Evidence considered
ACMG/AMP 2015 (PMID 25741868, Table 5) defines BP6 (supporting) as 'Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation'; per the governing rule for this group, only an exact-variant ClinVar expert-panel classification of Benign/Likely benign qualifies as a reputable-source assertion for BP6.
ClinVar variation 141819: aggregate Benign/Likely benign at review status 'criteria provided, multiple submitters, no conflicts' (2 stars), but expert_panel_submissions = 0; all 18-19 submitters are clinical laboratories (single-submitter SCVs, e.g., PreventionGenetics, Ambry Genetics, GeneDx, Labcorp, Mayo Clinic, ARUP).
The aggregate ClinVar label is composed entirely of ordinary laboratory submissions and therefore, per the governing rule, must never trigger BP6.
The NF1 CSPEC ruleset was empty in this case bundle, so no VCEP-specific BP6 handling was retrievable; the expert-panel-only restriction was applied.
Still missing
If a ClinGen expert panel (or other ClinGen-endorsed expert panel) later issues an exact-variant Benign/Likely benign classification for c.2022C>T, BP6 could be met at supporting strength; no such classification exists today.
PS2Not assessed: no confirmed de novo occurrence with verified parentage is reported for this variant.
Details ▾Hide ▴
Reasoning
No proband-level de novo observation and no parental (maternity/paternity) testing data exist anywhere in the case-evidence bundle. PS2 requires a confirmed de novo occurrence in a proband with the relevant phenotype, with paternity and maternity confirmed; with no proband family-testing information collected, the criterion cannot be evaluated and is returned as not_assessed.
Rule
Generic ACMG/AMP 2015 PS2 (PMID:25741868) - de novo with paternity and maternity confirmed; no NF1 VCEP-specific rule available (CSPEC v1.0 ruleset payload empty)
Evidence considered
Governing framework: NF1 VCEP CSPEC v1.0 (cspec, doc 1553923915) was consulted but its rule_payload is empty (framework_complete=false); no NF1-specific PS2 specification was retrievable, so generic ACMG/AMP 2015 applies.
PMID:25741868 (Richards et al. 2015) defines PS2 as de novo with paternity and maternity confirmed (strong, pathogenic).
Exhaustive keyword scan of the consolidated bundle (review_manifest, case_summary, source_registry, prefetch, evidence, literature_pass, vcep_materials, fulltext_map) for de novo, segregation, maternal, paternal, meiosis, proband, parent, family, pedigree, and inheritance returned zero matches; no proband or parental testing data exists for this case.
ClinVar (clinvar) record VCV000141819 contains 18 laboratory submissions (16 Benign, 1 benign, 1 Likely benign) with no expert-panel submissions and no criterion leads; no submission includes a de novo observation or parental testing result.
Still missing
No proband de novo occurrence of c.2022C>T reported
No parental (maternity/paternity) testing data for the proband
No proband clinical/phenotype context in the case bundle
PM6Not assessed: no assumed de novo occurrence is reported for this variant in any source.
Details ▾Hide ▴
Reasoning
No assumed de novo occurrence (i.e., de novo without confirmation of paternity and maternity) is reported for this variant in any source in the bundle. PM6 cannot be evaluated without a proband-level observation and the parental testing status of that observation; the criterion is returned as not_assessed pending such data.
Rule
Generic ACMG/AMP 2015 PM6 (PMID:25741868) - assumed de novo without confirmation of paternity and maternity; no NF1 VCEP-specific rule available (CSPEC v1.0 ruleset payload empty)
Evidence considered
Governing framework: NF1 VCEP CSPEC v1.0 (cspec) contains no PM6 specification (empty ruleset payload), so generic ACMG/AMP 2015 applies.
PMID:25741868 (Richards et al. 2015) defines PM6 as assumed de novo, but without confirmation of paternity and maternity (moderate, pathogenic).
Bundle-wide scan for de novo/segregation/family content found no reported de novo observation for this variant in any consulted source (prefetch, evidence, literature_pass, ClinVar submissions).
Still missing
No assumed de novo occurrence of c.2022C>T reported
Parental testing status of any proband observation is unknown
PP1Not assessed: no segregation data in affected family members were available.
Details ▾Hide ▴
Reasoning
No segregation data in affected family members is available: no pedigrees, no affected relatives tested, and no meioses counted appear anywhere in the case-evidence bundle. PP1 requires co-segregation of the variant with disease in multiple affected family members in a gene definitively known to cause the disease; with no family studies collected, the criterion is not assessable.
Rule
Generic ACMG/AMP 2015 PP1 (PMID:25741868) - co-segregation with disease in multiple affected family members; no NF1 VCEP-specific rule available (CSPEC v1.0 ruleset payload empty)
Evidence considered
Governing framework: NF1 VCEP CSPEC v1.0 (cspec) contains no PP1 specification (empty ruleset payload), so generic ACMG/AMP 2015 applies.
PMID:25741868 (Richards et al. 2015) defines PP1 as co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease (supporting, pathogenic).
Bundle-wide scan for segregation, family, pedigree, and meiosis content returned zero matches; no affected-family-member testing or informative meioses are documented for c.2022C>T.
ClinVar (clinvar) submissions for VCV000141819 contain no segregation observations; literature_pass.json lists no paper with a segregation theme and no paper mentioning this variant.
Still missing
No family segregation studies available for this variant
No affected relatives tested (zero informative meioses)
BS4Not assessed: no family testing data exist to establish lack of segregation in affected relatives.
Details ▾Hide ▴
Reasoning
BS4 requires documented lack of segregation in affected family members (i.e., an affected relative who does not carry the variant). No family testing data of any kind exists in the bundle, so non-segregation cannot be established. High gnomAD population frequency (v4.1 total AF 0.1647%, AFR 3.06%, 44 homozygotes; v2.1 total AF 0.2785%) is population-frequency evidence relevant to BA1/BS1, which are outside this group, and does not substitute for BS4 non-segregation data.
Rule
Generic ACMG/AMP 2015 BS4 (PMID:25741868) - lack of segregation in affected family members; no NF1 VCEP-specific rule available (CSPEC v1.0 ruleset payload empty)
Evidence considered
Governing framework: NF1 VCEP CSPEC v1.0 (cspec) contains no BS4 specification (empty ruleset payload), so generic ACMG/AMP 2015 applies.
PMID:25741868 (Richards et al. 2015) defines BS4 as lack of segregation in affected family members (strong, benign).
Bundle-wide scan for segregation/family/pedigree content returned zero matches; no affected family member has been shown to lack the variant, so BS4 is not met and cannot be assessed.
gnomAD v4.1 (gnomad_v4) shows total AF 0.1647% (2658/1613546 alleles) with 44 homozygotes and AFR AF 3.06% (2292/74908 alleles, 43 homozygotes); gnomAD v2.1 (gnomad_v2) shows total AF 0.2785% with 18 homozygotes. These frequencies inform population-frequency criteria (BA1/BS1, other groups) but are not segregation evidence and cannot satisfy BS4.
ClinVar (clinvar) submissions for VCV000141819 contain no segregation or family-testing observations.
Still missing
No non-segregation observations (affected relative without the variant)
BP2Not assessed: no allelic-phase or co-occurrence data with a pathogenic variant are reported.
Details ▾Hide ▴
Reasoning
BP2 as defined in ACMG/AMP 2015 (PMID:25741868, Table 5) requires the variant to be 'observed in trans with a pathogenic variant for a fully dominant disease/disorder; or observed in cis with a pathogenic variant in any inheritance pattern'. NF1/neurofibromatosis type 1 is fully dominant (CSPEC NF1 v1.0 metadata), so the criterion is structurally applicable, but no allelic-phase evidence exists for this variant in any source in the case bundle: ClinVar VCV000141819 contains 18-19 submissions, all Benign (16), benign (1), or Likely benign (1), with no expert-panel submissions and no reported co-occurrence or phase with a pathogenic NF1 variant (submission audit: usable_for_criterion_leads = 0); no literature reporting this specific variant was identified; and no proband/family observation of the variant in cis or trans with a pathogenic variant is documented. gnomAD population homozygosity (e.g., 44 homozygotes in gnomAD v4.1) reflects population frequency in a largely unaffected cohort and is not phase evidence with a pathogenic variant. Evidence is insufficient to apply BP2; the criterion is therefore not assessed pending phase/co-occurrence data.
Rule
BP2: Observed in trans with a pathogenic variant for a fully dominant disease/disorder; or observed in cis with a pathogenic variant in any inheritance pattern (PMID:25741868, Table 5)
Evidence considered
ACMG/AMP 2015 (PMID 25741868, Table 5) defines BP2 as 'Observed in trans with a pathogenic variant for a fully dominant disease/disorder; or observed in cis with a pathogenic variant in any inheritance pattern' (supporting).
CSPEC NF1 v1.0 metadata confirms neurofibromatosis type 1 is autosomal dominant, satisfying BP2's fully-dominant-disease premise for the trans clause.
ClinVar variation 141819 was reviewed for phase/co-occurrence evidence: 16 Benign, 1 benign, and 1 Likely benign clinical-laboratory submissions, no expert-panel submissions, no criterion leads, and no phase/co-occurrence information (clinvar_submission_audit: submissions_total 20, usable_for_criterion_leads 0).
gnomAD v4.1 population data (overall AF 0.165%, 44 homozygotes; AFR AF 3.06%, 43 homozygotes) reflects population frequency in unaffected individuals and is not phase evidence with a pathogenic variant; not used to satisfy BP2.
Still missing
No allelic-phase data: the variant has not been observed in cis or in trans with a pathogenic NF1 variant in any affected proband or family.
No ClinVar submission for this variant provides co-occurrence, segregation, or phase details (all submissions are aggregate Benign/Likely benign classifications without phase information; usable_for_criterion_leads = 0).
No publication reporting this specific variant (c.2022C>T / p.Ser674=) with phase or co-occurrence information was identified.
Not applicable · 9· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: this synonymous change leaves the protein unchanged, so no loss-of-function mechanism such as nonsense-mediated decay is triggered.
Details ▾Hide ▴
Reasoning
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001042492.2:c.2022C>T in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Ser674=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
PS1N/ANot applicable: the synonymous change produces no altered amino acid to compare with previously established pathogenic variants.
Details ▾Hide ▴
Reasoning
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001042492.2:c.2022C>T in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Ser674=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM1N/ANot applicable: no altered residue exists to evaluate for a mutational hotspot or critical functional domain.
Details ▾Hide ▴
Reasoning
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001042492.2:c.2022C>T in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Ser674=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM3N/ANot applicable: NF1 is autosomal dominant, so the recessive-disorder premise of PM3 does not apply.
Details ▾Hide ▴
Reasoning
PM3 as defined in ACMG/AMP 2015 (PMID:25741868, Table 4) applies only 'for recessive disorders, detected in trans with a pathogenic variant'. The governing framework for this case is the ClinGen Neurofibromatosis and Schwannomatosis Expert Panel specification for NF1 v1.0 (CSPEC doc 1553923915, precedence rank 1), whose gene-level metadata designates neurofibromatosis type 1 (MONDO:0018975) as 'Autosomal dominant inheritance'. Because NF1 is a fully dominant disorder, the recessive-disorder premise of PM3 is not satisfied, so the criterion is not applicable regardless of any phase observations. Caveat: the VCEP rule payload was empty in this case bundle (framework_complete: false, rule_payload: {}), so no VCEP-specific PM3 modification could be retrieved; under the generic definition, a trans observation of this variant with a pathogenic NF1 variant would be evaluated under BP2 (trans with a pathogenic variant in a fully dominant disease), not PM3.
Rule
PM3: For recessive disorders, detected in trans with a pathogenic variant (PMID:25741868, Table 4)
Evidence considered
CSPEC NF1 v1.0 ruleset metadata (vcep_materials.json -> final_classification_framework.raw_rule_origin) designates preferredModeOfInheritance 'Autosomal dominant inheritance' for neurofibromatosis type 1 (MONDO:0018975).
ACMG/AMP 2015 (PMID 25741868, Table 4) defines PM3 as 'For recessive disorders, detected in trans with a pathogenic variant' (moderate), requiring a recessive disorder context.
The NF1 VCEP rule payload was empty in this case bundle (framework_complete: false), so no NF1 VCEP-specific PM3 rule was retrievable; the generic PM3 definition was applied.
PM4N/ANot applicable: the synonymous change causes no protein length alteration for this criterion to evaluate.
Details ▾Hide ▴
Reasoning
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001042492.2:c.2022C>T in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Ser674=). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
PM5N/ANot applicable: no missense change occurs, so there is nothing to compare with pathogenic missense at this residue.
Details ▾Hide ▴
Reasoning
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001042492.2:c.2022C>T in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Ser674=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PP2N/ANot applicable: this missense-only criterion does not apply to a synonymous variant.
Details ▾Hide ▴
Reasoning
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001042492.2:c.2022C>T in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Ser674=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP1N/ANot applicable: this criterion concerns missense variants, and the change is synonymous.
Details ▾Hide ▴
Reasoning
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001042492.2:c.2022C>T in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Ser674=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP3N/ANot applicable: no in-frame indel in a repetitive region is involved.
Details ▾Hide ▴
Reasoning
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001042492.2:c.2022C>T in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Ser674=). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
AF 0.0016 · 2658 / 1,613,546 alleles · 44 hom · FAF 0.03
African/African American2292 / 74,908
0.03143 hom
Remaining individuals147 / 62,472
0.00241 hom
Admixed American123 / 59,940
0.0021
Middle Eastern8 / 6,056
0.0013
South Asian11 / 91,068
0.00012
European (non-Finnish)77 / 1,179,732
6.5e-05
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0028 · 785 / 281,884 alleles · 18 hom · FAF 0.027
African/African American720 / 24,926
0.02918 hom
Admixed American46 / 35,352
0.0013
Remaining individuals3 / 7,204
0.00042
South Asian4 / 30,614
0.00013
European (non-Finnish)12 / 128,396
9.3e-05
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, European (Finnish).
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.0016473; MAF= 0.16473%, 2658/1613546 alleles, homozygotes = 44) and has highest observed frequency in the African/African American population (AF= 0.0305975; MAF= 3.05975%, 2292/74908 alleles, homozygotes = 43); grpmax FAF= 0.029553.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00278483; MAF= 0.27848%, 785/281884 alleles, homozygotes = 18) and has highest observed frequency in the African/African American population (AF= 0.0288855; MAF= 2.88855%, 720/24926 alleles, homozygotes = 18); grpmax FAF= 0.0269323.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0023894862604540022, 44/18414 alleles, homozygotes = 0).
BP7SupportingMet (supporting): synonymous change, no predicted splice impact (SpliceAI max delta 0.009), and high population frequency indicating no strong conservation.
Details ▾Hide ▴
Reasoning
All three BP7 components are satisfied. (1) Synonymous variant: Mutalyzer normalization confirms NM_001042492.2:c.2022C>T is synonymous, NP_001035957.1:p.(Ser674=). (2) Splicing prediction algorithms do not predict impact to the splice consensus sequence nor creation of a new splice site: SpliceAI max delta = 0.009 (DS_AG 0.009, DS_AL 0.002, DS_DG 0.000, DS_DL 0.002), below the 0.2 recommended cutoff of the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751) and below the 0.1 threshold of the lab generic calibration; the variant is in the exon body (~22 nt from the exon's 5' end), not at a canonical splice position, and predicted cryptic splice gains are distant and negligible (DP_DG 370, DP_DL 229). (3) Nucleotide not highly conserved: the variant is a common polymorphism with high allele frequency and multiple homozygotes (gnomAD v4.1 AF 0.165% overall, 44 homozygotes, AFR AF 3.06% with 43 homozygotes; gnomAD v2.1 AF 0.278%, 18 homozygotes; gnomAD-Canada AF 0.239%), indicating the position is not under strong purifying selection.
Rule
Generic ACMG/AMP 2015 BP7 (Richards et al., PMID 25741868): a synonymous (silent) variant for which splicing prediction algorithms do not predict impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Default strength: supporting.
Evidence considered
Synonymous status: Mutalyzer normalization (prefetch) confirms NM_001042492.2:c.2022C>T is a synonymous variant, NP_001035957.1:p.(Ser674=).
SpliceAI (spliceai) max delta score 0.009 - no impact predicted on the splice consensus sequence and no new splice site (DS_AG 0.009 acceptor gain, DS_DG 0.000 donor gain, DS_DL 0.002, DS_AL 0.002); this is below the 0.2 cutoff recommended in the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751) and below the 0.1 threshold of the lab generic calibration (generic_acmg_combination_rules).
The variant is in the exon body (transcript-relative g.2406; exon spans c.2001-2250), about 22 nt from the exon's 5' end and not within any canonical splice consensus sequence; SpliceAI predicted splice-gain events are distant (DP_DG 370, DP_DL 229) with negligible delta scores.
Nucleotide not highly conserved: gnomAD v4.1 (gnomad_v4) total AF 0.0016473 (2658/1613546 alleles, 44 homozygotes) with African/African American AF 0.0305975 (2292/74908 alleles, 43 homozygotes); gnomAD v2.1 (gnomad_v2) total AF 0.00278483 (785/281884 alleles, 18 homozygotes); gnomAD-Canada (gnomad_canada) AF 0.002389 (44/18414 alleles). A nucleotide position carrying a variant at these frequencies with multiple homozygotes is not under strong purifying selection, i.e., not highly conserved.
Still missing
No direct conservation score (e.g., phyloP/GERP) was present in the case bundle; the 'nucleotide not highly conserved' component of BP7 is supported by the variant's high population frequency with multiple homozygotes in gnomAD rather than a direct conservation metric.
PP3Not met: SpliceAI max delta 0.009 is far below the 0.2 cutoff for predicted splice impact.
Details ▾Hide ▴
Reasoning
No computational evidence supports a deleterious effect. On the splice-impact path (the applicable path for this synonymous variant), SpliceAI predicts no significant splice impact: max delta score = 0.009 (DS_AG 0.009, DS_AL 0.002, DS_DG 0.000, DS_DL 0.002), more than 20-fold below the 0.2 cutoff recommended in the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751) and below the >0.2 threshold that the lab generic calibration assigns PP3 for non-missense variants. The missense in-silico path does not apply: the variant is synonymous p.(Ser674=) (Mutalyzer normalization); REVEL returned no score (found: false; REVEL covers missense substitutions only), BayesDel has no verified published threshold and is unusable for PP3/BP4 per the generic calibration, and aGVGD is not present in this case. PP3 not met.
Rule
Generic ACMG/AMP 2015 PP3 (Richards et al., PMID 25741868) with lab generic in-silico calibration: PP3 met only if computational evidence supports a deleterious effect (SpliceAI max delta > 0.2 for synonymous/non-missense variants; REVEL > 0.750 for missense).
Evidence considered
SpliceAI lookup (spliceai) for NM_001042492.2:c.2022C>T returned max delta score = 0.009 with all four delta scores far below impact thresholds (DS_AG 0.009, DS_AL 0.002, DS_DG 0.000, DS_DL 0.002).
The SpliceAI publication (Jaganathan et al. 2019, PMID 30661751) recommends a delta-score cutoff of 0.2 for high sensitivity; the observed max delta of 0.009 is >20-fold below this, so no splice impact is predicted.
Lab generic calibration (generic_acmg_combination_rules) assigns PP3 for synonymous/non-missense variants only when SpliceAI max delta > 0.2; 0.009 does not meet this.
REVEL lookup for chr17-31226455-C-T returned no score (found: false), expected for a synonymous variant because REVEL is a missense-prediction resource.
BayesDel is not usable for PP3/BP4: no verified published threshold is available to this pipeline (generic_acmg_combination_rules); aGVGD data is not present in this case bundle.
Still missing
Missense in-silico path (REVEL/BayesDel/aGVGD) is not applicable to this synonymous variant and none produced a score; the splice-impact path is fully covered by SpliceAI.
BP4Not met: the only computational no-impact line (SpliceAI) is already counted under BP7 and cannot be double-counted here.
Details ▾Hide ▴
Reasoning
BP4 requires multiple lines of computational evidence suggesting no impact on the gene/gene product. The only available computational no-impact line is SpliceAI (max delta 0.009, below the 0.1 threshold of the generic calibration and the 0.2 cutoff of the SpliceAI publication). That same single prediction is the splice-impact basis of BP7 for this synonymous variant, and the same prediction must not be double-counted across BP4 and BP7. No independent second line exists: REVEL is not applicable to synonymous variants (lookup found: false), BayesDel has no verified threshold, and aGVGD is unavailable. BP4 therefore not met; the benign computational evidence is captured under BP7.
Rule
Generic ACMG/AMP 2015 BP4 (Richards et al., PMID 25741868): multiple lines of computational evidence suggest no impact on gene/gene product; lab generic calibration: SpliceAI max delta < 0.1 for non-missense variants. Not double-counted with BP7 for the same prediction.
Evidence considered
SpliceAI max delta 0.009 for c.2022C>T is below the generic calibration BP4 threshold of 0.1 (generic_acmg_combination_rules) and below the 0.2 cutoff of the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751), i.e., exactly one line of no-impact computational evidence.
Applying the same SpliceAI no-impact prediction to both BP4 and BP7 would double-count a single prediction across two criteria; per this group's adjudication rule the prediction is applied under BP7 (the variant-type-specific criterion for synonymous variants), and BP4 is not independently met.
REVEL returned no score (found: false) for this synonymous variant and cannot contribute a second line; BayesDel is uncalibrated (generic_acmg_combination_rules) and aGVGD is not present in this case.
Still missing
No second, independent line of computational no-impact evidence is available for this synonymous variant (REVEL/BayesDel/aGVGD not applicable or uncalibrated); only SpliceAI qualifies, and it is applied under BP7 without double-counting.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
9 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Richards et al. 2015 is the joint ACMG/AMP consensus guideline that defines the four criteria adjudicated in this group: PS2 (de novo, paternity and maternity confirmed; strong pathogenic), PM6 (assumed de novo without confirmation of paternity and maternity; moderate pathogenic), PP1 (co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease; supporting pathogenic), and BS4 (lack of segregation in affected family members; strong benign). It was consulted as the governing generic framework because the NF1 VCEP CSPEC v1.0 ruleset payload is empty. It contains no mention of NF1 c.2022C>T and provides no variant-specific de novo or segregation data.
→ BA1 · stand-alone benign→ BS1 · supporting→ BS2 · supportingDoes not name this variant
Assays that assess the impact of variants at the mRNA level can be highly informative when evaluating the effects of variants at splice junctions and within coding sequences, untranslated regions, as well as deeper intronic regions (e.g. mRNA stability, processing or translation). Technical approaches include direct analysis of RNA and/or cDNA derivatives and in vitro minigene splicing assays.
Location Local full-text extraction (publications/25741868.txt) contains only the introduction/methods fragment and is truncated before the criteria tables; the PS2/PM6/PP1/BS4 definitions above are from Tables 5-6 of the published guideline as reflected in the pipeline's generic_acmg_combination_rules source basis. No verbatim quote could be verified from the local extraction, so none is asserted.
Context ACMG/AMP 2015 joint consensus recommendation (Richards et al., Genet Med 2015), expert-panel-derived criteria framework for sequence variant classification.
Other recorded publications
A systematic approach to assessing the clinical significance of genetic variants.
Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors.
Radtke HB et al. · 2007
NSGC recommendations for genetic counseling in neurofibromatosis type 1. The document establishes that NF1 is a clinical diagnosis based on the 1987 NIH diagnostic criteria and reviews NF1 clinical features, inheritance, and counseling practice. It contains no variant-level data: the exact variant c.2022C>T / p.Ser674= was not found in the full text. It was triaged as a candidate source for PS4/PP5 but cannot support either criterion for this variant.
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
Hampel H et al. · 2015
ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. It lists NF1-associated signs (e.g., cafe-au-lait macules and other NF1 signs) among referral indications for genetic testing in the context of childhood brain tumors, confirming NF1 as a clinically recognizable single-gene phenotype. The document contains no variant-level data: c.2022C>T / p.Ser674= was not found in the full text. It was triaged as a candidate source for PS4/PP5 but cannot support either criterion for this variant.
Café-au-lait macules and/or other signs of NF1, or hypopigmented skin lesions
Full-text extraction, referral indications section (brain tumor criteria table; Hampel et al. 2015, Genet Med 17(1):70-87)
Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis-Practice Resource of the National Society of Genetic Counselors.
NSGC practice resource for genetic counseling in neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis. It states that NF1 is most often diagnosed based on clinical features consistent with the formal diagnostic criteria, typically manifesting in early childhood, and reviews the clinical phenotype and counseling approach. The document contains no variant-level data: c.2022C>T / p.Ser674= was not found in the full text. It was triaged as a candidate source for PS4/PP5 but cannot support either criterion for this variant.
NF1 is most often diagnosed based on clinical features consistent with the formal diagnostic criteria. Clinical features typically begin to appear in early childhood, and most affected individuals meet diagnostic criteria by age 8
The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.0016473; MAF= 0.16473%, 2658/1613546 alleles, homozygotes = 44) and has highest observed frequency in the African/African American population (AF= 0.0305975; MAF= 3.05975%, 2292/74908 alleles, homozygotes = 43); grpmax FAF= 0.029553.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00278483; MAF= 0.27848%, 785/281884 alleles, homozygotes = 18) and has highest observed frequency in the African/African American population (AF= 0.0288855; MAF= 2.88855%, 720/24926 alleles, homozygotes = 18); grpmax FAF= 0.0269323.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0023894862604540022, 44/18414 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Benign (16 clinical laboratories) and as benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 141819)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104420496, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 7.1.0.
The current version is 11.0.07.
Re-running queues a fresh interpretation; the result replaces this page when complete.
Re-runs are not free. Blank draws on today's public interpretation allowance; with a code, it uses one of that code's uses.