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.
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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 · 2
BA1Stand alone
BA1 · stand alone
Met (stand-alone benign): South Asian allele frequency 1.91% in gnomAD v4.1 (2.01% in v2.1) is far too common for a pathogenic NF1 allele.
BP4Supporting
BP4 · supporting
Met (supporting): SpliceAI predicts no splice impact, with max delta score 0.004, consistent with a benign effect.
Recorded classification: Benign
Benign: South Asian allele frequency ~1.91% in gnomAD v4.1 meets BA1 at stand-alone strength; SpliceAI max delta 0.004 adds BP4 supporting.
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
1,847 / 1,613,986 alleles
gnomAD v4.1: 1,847 / 1,613,986 alleles. Recorded AF 0.00114437. Recorded homozygote count 22.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00222805; MAF= 0.22281%, 630/282758 alleles, homozygotes = 6) and has highest observed frequency in the South Asian population (AF= 0.0201228; MAF= 2.01228%, 616/30612 alleles, homozygotes = 6); grpmax FAF= 0.0188075.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.001954185213331886, 36/18422 alleles, homozygotes = 0).
No COSMIC evidence statement is recorded in this case.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen NF1 VCEP v1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 2 not met · 13 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
NM_001042492.2:c.*4T>C is a 3' UTR SNV located 4 nucleotides downstream of the NF1 stop codon (most_severe_consequence='3_prime_UTR_variant' per VEP annotation), with no predicted amino-acid change (NP_001035957.1:p.?).
None of PVS1, PM4, or BP3 apply because each requires a specific structural variant class (null variant for PVS1; in-frame indel or stop-loss for PM4; in-frame indel in a non-critical repeat region for BP3) that this non-coding substitution does not satisfy.
The NF1 ClinGen CSPEC (Neurofibromatosis and Schwannomatosis EP v1.0) provided no structured, gene-specific rule payload overriding this generic ACMG/SVI conclusion for UTR variants, so the generic PVS1/PM4/BP3 preconditions from the ClinGen SVI framework (PMC6185798) were applied as fallback.
NM_001042492.2:c.*4T>C is located in the 3' untranslated region (indicated by the '*' offset from the stop codon), producing no amino acid change (protein annotation NP_001035957.1:p.?, variant_class null). All five codon/residue/domain-level criteria (PS1, PM1, PM5, PP2, BP1) presuppose a missense amino acid substitution at a specific codon and are therefore not_applicable to this variant.
PS3/BS3 require validated functional assay evidence (e.g. splicing minigene, RT-PCR, biochemical/protein activity assay) directly assessing the variant. The case-evidence bundle contains no functional study of NM_001042492.2:c.*4T>C; all linked PMIDs are guideline/policy documents, a leukemia case series, and cancer-risk cohort papers with no assay data on this variant. Both criteria are therefore not_assessed rather than not_met, pending identification of a qualifying functional study.
Variant is NM_001042492.2:c.*4T>C, a 3' UTR substitution 4 nt downstream of the stop codon in NF1 - not missense, not synonymous, and not a canonical splice consensus variant.
SpliceAI predicts no splice impact (max delta score 0.004), so BP4 is met at supporting strength and PP3 is not met.
BP7 (synonymous, no splice effect) does not apply because this is a 3' UTR variant, not a synonymous coding change.
No NF1 ClinGen VCEP gene-specific PP3/BP4 lookup table content was available in vcep_materials.json to override the generic SpliceAI-based assessment.
Population evidence supports BA1 for NF1 c.*4T>C because its reproducible South Asian frequency is approximately 2%, with multiple observed homozygotes.
No criteria match.
Met · 2
BA1Stand aloneMet (stand-alone benign): South Asian allele frequency 1.91% in gnomAD v4.1 (2.01% in v2.1) is far too common for a pathogenic NF1 allele.
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Reasoning
The NF1 c.*4T>C allele is far too common for a pathogenic NF1 allele: gnomAD v4.1 shows South Asian AF 1.9147% (1,744/91,084 alleles; 22 homozygotes) with grpmax FAF 1.8399%, independently consistent with gnomAD v2.1 South Asian AF 2.0123% (616/30,612; 6 homozygotes). This satisfies the NF1 VCEP population-frequency benign criterion (BA1).
Rule
NF1 VCEP BA1 population-frequency criterion
Evidence considered
The applicable framework is ClinGen Neurofibromatosis and Schwannomatosis Expert Panel NF1 specification version 1.0.
gnomAD v4.1: overall AF 0.1144% (1,847/1,613,986), South Asian AF 1.9147% (1,744/91,084), 22 South Asian homozygotes, and South Asian grpmax FAF 1.8399%.
gnomAD v2.1 independently reports South Asian AF 2.0123% (616/30,612), 6 South Asian homozygotes, and grpmax FAF 1.8808%.
gnomAD-Canada v1.0 also reports enrichment in the South Asian subset: 35/1,362 alleles (AF 2.5698%; FAF95 1.8993%).
BP4SupportingMet (supporting): SpliceAI predicts no splice impact, with max delta score 0.004, consistent with a benign effect.
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Reasoning
SpliceAI predicts no meaningful splice impact for NM_001042492.2:c.*4T>C (max delta score 0.004, all four delta scores <=0.004), well below the calibrated donor/acceptor gain-or-loss threshold used to flag possible splice disruption. This is a 3' UTR variant with no missense consequence, so no missense in-silico prediction path applies. The computational evidence is consistent with a benign impact, supporting BP4 at supporting strength.
Evidence considered
SpliceAI Lookup: DS_AG=0.00, DS_AL=0.001, DS_DG=0.00, DS_DL=0.004, max delta=0.004 for NM_001042492.2:c.*4T>C, indicating no predicted disruption of splice donor/acceptor sites.
Variant lies in the 3' UTR, 4 nt beyond the stop codon; no missense change is created, so REVEL/BayesDel/aGVGD computational missense evidence does not apply here.
PM2Not met: the allele is common in population databases, with South Asian gnomAD v4.1 frequency 1.91%.
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Reasoning
PM2 is not met because this allele is common in population reference datasets, particularly in South Asian individuals (gnomAD v4.1 AF 1.9147%; v2.1 AF 2.0123%).
Rule
NF1 VCEP PM2 rarity/absence criterion
Evidence considered
The allele is observed at South Asian AF approximately 1.9% to 2.0% in two gnomAD releases and at 2.5698% in the South Asian subset of gnomAD-Canada; it is neither absent nor rare in population data.
PP3Not met: SpliceAI max delta 0.004, far below the ~0.2 threshold used to flag splice impact.
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Reasoning
NM_001042492.2:c.*4T>C is a 3' UTR variant (4 bp downstream of the stop codon), not a missense or splice-region substitution near a canonical consensus site. SpliceAI (the applicable computational tool for this variant type) predicts no splice impact: max delta score 0.004 (DS_AG 0.00, DS_AL 0.001, DS_DG 0.00, DS_DL 0.004), far below any calibrated pathogenic threshold (typically >=0.2). No missense in-silico predictors (REVEL/BayesDel/aGVGD) apply since this is not a missense variant. No NF1 VCEP gene-specific PP3/BP4 lookup table was found in vcep_materials for this position. PP3 is not met.
Evidence considered
SpliceAI Lookup for NM_001042492.2:c.*4T>C: DS_AG=0.00, DS_AL=0.001, DS_DG=0.00, DS_DL=0.004, max delta score=0.004 (all scores near zero, far below the 0.2 pathogenic-supporting threshold commonly used for PP3 splice application).
Variant is located in the 3' UTR (c.*4 position), not a missense change, so REVEL/BayesDel/aGVGD missense predictors are not applicable to this variant type.
No NF1 ClinGen VCEP gene-specific PP3/BP4 lookup spreadsheet was present in vcep_materials.json for this case; framework note only references the general NF1 cspec ruleset with no rule_payload content.
PS2Not assessed: no de novo occurrence with parental confirmation or proband phenotype data was reported.
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Reasoning
No case-level evidence establishes that NM_001042492.2:c.*4T>C occurred de novo in an affected individual. There are no parental genotypes, parentage confirmation, or proband phenotype data.
Rule
Generic ACMG/AMP fallback: PS2 requires a confirmed de novo occurrence in a patient with the disease and no family history; the required case and parental data are absent.
Evidence considered
The NF1 ClinGen specification is present but its retrieved rule payload is empty and marked framework_complete=false; therefore no usable NF1-specific PS2 rule was available.
The consolidated case evidence contains no proband, parental-testing, parentage, or de novo occurrence data for NM_001042492.2:c.*4T>C.
Still missing
Obtain proband genotype and phenotype information.
Obtain maternal and paternal testing for the exact variant, with parentage confirmation if available.
Document whether the proband phenotype is consistent with NF1-related disease.
PS3Not assessed: no functional assay data (splicing, RNA, or protein) for this variant were available.
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Reasoning
No functional/validated assay data (splicing reporter, minigene, RT-PCR, protein/GTPase activity assay, or other case-control functional study) for NF1 c.*4T>C (3' UTR variant) were found in the case evidence bundle, prefetch, literature_pass, or vcep_materials. The papers linked in this case (leukemia case series, cancer testing guidelines, WHO classification, cancer risk assessment recommendations) are not functional characterization studies of this variant and do not mention it. The NF1 VCEP (ClinGen NF/Schwannomatosis EP v1.0) specification text was not available in vcep_materials (rule_payload empty, no PS3/BS3 threshold details retrieved), so no VCEP-specific PS3/BS3 calibration could be applied either.
Still missing
No functional assay publication identified for NF1 c.*4T>C in the current literature pass or full-text set
NF1 VCEP PS3/BS3 assay-strength calibration table not retrieved into vcep_materials for this case
PS4Not assessed: no case-control or affected-series enrichment data for this exact variant were available.
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Reasoning
No exact-variant case-control enrichment or statistically evaluable affected-case series was identified. The reviewed papers address NF1 biology or somatic NF1 alterations in AML, not NM_001042492.2:c.*4T>C in affected versus control individuals.
Rule
NF1 VCEP Specification v1.0 was prioritized; no applicable PS4-specific rule was available in the supplied framework. Do not apply PS4 without exact-variant enrichment evidence.
Evidence considered
The NF1 VCEP specification is identified for this case, but the supplied framework contains no structured PS4-specific threshold or rule.
ClinVar identifies an exact variant record, but its submissions are ordinary clinical laboratory submissions and do not provide case-control counts or phenotype-stratified enrichment data.
PMID:10678181 is a murine Nf1/Gmcsf leukemogenesis study and does not mention the exact human variant.
PMID:23460398 screened de novo AML for somatic NF1 alterations and does not report the exact c.*4T>C variant as an affected-case observation or a case-control association.
Still missing
A phenotype-defined cohort or case-control study reporting NM_001042492.2:c.*4T>C (or NC_000017.10:g.29701177T>C) with affected and control counts, ancestry, and statistical analysis.
PM6Not assessed: no presumed de novo occurrence in an affected individual was reported.
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Reasoning
No case-level evidence reports NM_001042492.2:c.*4T>C as a presumed de novo variant in an affected individual without parental confirmation.
Rule
Generic ACMG/AMP fallback: PM6 requires a presumed de novo occurrence in an affected individual when parental confirmation is unavailable; no such occurrence is documented.
Evidence considered
The NF1 ClinGen specification is present but its retrieved rule payload is empty and marked framework_complete=false; therefore no usable NF1-specific PM6 rule was available.
The consolidated case evidence contains no proband, parental-testing, or presumed de novo occurrence data for NM_001042492.2:c.*4T>C.
Still missing
Obtain proband genotype and phenotype information.
Obtain parental testing or, if unavailable, a documented presumed de novo report for the exact variant.
Document phenotype consistency with NF1-related disease.
PP1Not assessed: no family segregation data, affected-relative genotypes, or meiosis counts were available.
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Reasoning
No informative family segregation data, affected-relative genotypes, phenotypes, or meiosis counts are available for NM_001042492.2:c.*4T>C.
Rule
Generic ACMG/AMP fallback: PP1 requires cosegregation of the variant with disease in informative affected relatives; no segregation dataset is available.
Evidence considered
The NF1 ClinGen specification is present but its retrieved rule payload is empty and marked framework_complete=false; therefore no usable NF1-specific PP1 rule was available.
The consolidated case evidence contains no family segregation observations or informative meiosis counts for NM_001042492.2:c.*4T>C.
Still missing
Obtain pedigree structure, phenotype status, and genotype results for informative relatives.
Document the number of informative cosegregations/meioses and any phenocopies.
PP4Not assessed: no NF1-specific proband phenotype data were provided.
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Reasoning
No proband-level phenotype, phenotype specificity assessment, or confirmation that the tested individual has a phenotype highly specific for NF1 was supplied.
Rule
NF1 VCEP Specification v1.0 was prioritized; no applicable PP4-specific rule was available in the supplied framework. Do not apply PP4 from gene-disease association or ClinVar condition labels alone.
Evidence considered
The NF1 VCEP specification is identified for this case, but the supplied framework contains no structured PP4-specific rule.
ClinVar condition labels are submitter-level record annotations, not a phenotype description for the proband under assessment.
Still missing
Proband phenotype, diagnostic evaluation, age, and exclusion of alternative molecular explanations sufficient to assess phenotype specificity.
PP5Not assessed: no expert-panel record classifies this exact variant as pathogenic or likely pathogenic.
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Reasoning
The exact ClinVar record has no expert-panel submission classified Pathogenic or Likely pathogenic. Therefore PP5 cannot be applied.
Rule
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Evidence considered
The exact ClinVar record reports zero expert-panel submissions. Its Pathogenic/Likely pathogenic criterion is not met by ordinary laboratory submissions or aggregate labels.
Still missing
An exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion.
BS2Not assessed: the 22 reported homozygotes were not confirmed as comprehensively phenotyped and unaffected.
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Reasoning
Although gnomAD reports 22 South Asian homozygotes, the supplied population datasets do not establish that these specific individuals were comprehensively phenotyped and unaffected for NF1. Homozygote counts therefore cannot independently support BS2.
Rule
BS2 requires observation in appropriately phenotyped unaffected individual(s)
Evidence considered
gnomAD v4.1 reports 22 South Asian homozygotes and gnomAD v2.1 reports 6, but neither supplied record provides individual NF1 phenotype assessment.
Still missing
Phenotype- and age-documented unaffected homozygous or heterozygous individuals are required to assess BS2.
BS3Not assessed: no functional assay data refuting a damaging effect for this variant were available.
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Reasoning
No functional/validated assay data refuting a damaging effect for NF1 c.*4T>C were found in the case evidence bundle, prefetch, literature_pass, or vcep_materials. None of the linked publications report a functional (splicing, RNA, protein) assay of this specific 3' UTR variant. Population/frequency and ClinVar submission evidence exist elsewhere in the bundle but are outside the scope of PS3/BS3 (assay-based evidence only) and are adjudicated under other criteria groups.
Still missing
No functional assay publication identified for NF1 c.*4T>C showing normal/wild-type function
NF1 VCEP PS3/BS3 assay-strength calibration table not retrieved into vcep_materials for this case
BS4Not assessed: no unaffected-carrier or affected-non-carrier genotypes or pedigree data were available.
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Reasoning
No informative non-segregation evidence is available: the record contains no genotype-confirmed unaffected carriers, affected non-carriers, or pedigree data for NM_001042492.2:c.*4T>C.
Rule
Generic ACMG/AMP fallback: BS4 requires convincing lack of cosegregation with disease in informative relatives; no such data are documented.
Evidence considered
The NF1 ClinGen specification is present but its retrieved rule payload is empty and marked framework_complete=false; therefore no usable NF1-specific BS4 rule was available.
The consolidated case evidence contains no familial non-segregation observations for NM_001042492.2:c.*4T>C.
Still missing
Obtain pedigree structure, genotype results, and age-appropriate phenotype assessments for informative relatives.
Document any confirmed non-segregation while accounting for NF1 age-related expression and variable expressivity.
BP2Not assessed: no individual-level co-occurrence or phased trans observations were available.
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Reasoning
No individual-level co-occurrence data are provided for NM_001042492.2:c.*4T>C. In particular, there is no documented cis observation with a pathogenic NF1 variant in an affected individual, nor any phased trans observation that could be evaluated under an applicable disease model.
Rule
Generic ACMG/AMP BP2 requires a documented qualifying co-occurrence; no such observation is available in this case.
Evidence considered
The NF1 ClinGen Neurofibromatosis and Schwannomatosis Expert Panel framework specifies neurofibromatosis type 1 with autosomal dominant inheritance.
The consolidated case evidence supplies population and ClinVar summary data but no individual-level co-occurrence or phase observation for this variant.
Still missing
Individual-level genotype data identifying any second NF1 variant and its pathogenicity classification.
Phase evidence establishing cis or trans configuration and the individual's phenotype/affected status.
BP5Not assessed: no evidence of an alternate cause of the phenotype was available.
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Reasoning
No proband-level phenotype or independent molecular diagnosis was supplied from which an alternate cause of the phenotype could be established.
Rule
NF1 VCEP Specification v1.0 was prioritized; no applicable BP5-specific rule was available in the supplied framework. Do not apply BP5 without a demonstrated alternate molecular cause for the proband phenotype.
Evidence considered
The NF1 VCEP specification is identified for this case, but the supplied framework contains no structured BP5-specific rule or alternate-diagnosis evidence.
Still missing
Proband phenotype and comprehensive molecular findings demonstrating an alternative diagnosis that explains the phenotype.
BP6Not assessed: no expert-panel record classifies this exact variant as benign or likely benign.
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Reasoning
The exact ClinVar record has no expert-panel submission classified Benign or Likely benign. Therefore BP6 cannot be applied.
Rule
Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification.
Evidence considered
The exact ClinVar record reports zero expert-panel submissions. Its Benign/Likely benign aggregate and ordinary laboratory submissions cannot trigger BP6.
Still missing
An exact-variant ClinVar expert-panel Benign or Likely benign assertion.
Not applicable · 11· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: as a 3' UTR change, it alters no protein-coding sequence, creates no premature stop, and affects no splice consensus site.
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Reasoning
NM_001042492.2:c.*4T>C is located at position +4 downstream of the stop codon, in the 3' UTR of NF1 (most_severe_consequence = 3_prime_UTR_variant per VEP annotation; protein prediction NP_001035957.1:p.? indicates no protein-coding change). The NF1 CSPEC (ClinGen Neurofibromatosis and Schwannomatosis EP v1.0) does not provide a structured PVS1 rule payload applicable here, so the generic ClinGen SVI PVS1 decision framework (PMC6185798) was consulted as fallback per gene-context guidance. PVS1 is restricted to null-variant classes: nonsense, frameshift, canonical +/-1,2 splice-site, initiation-codon, or single/multi-exon deletion variants predicted to trigger NMD or truncate/eliminate a functionally critical protein region. A 3' UTR SNV does not alter the coding sequence, does not create a premature termination codon, does not affect canonical splice consensus sequences, and does not remove any exon. The variant-level generic PVS1 scaffold explicitly classifies this as consequence_class 'unknown' / variant_bucket 'other' and states apply_generic_pvs1_framework = false because it falls outside all default PVS1 null-variant buckets. Therefore PVS1 (and NMD, exon-importance, and truncation-length considerations that underlie it) is not applicable to this variant.
Rule
PVS1 not applicable: variant is a 3' UTR SNV (no coding-sequence, splice, initiation-codon, or exon-deletion effect); does not meet any PVS1 null-variant class per ClinGen SVI decision tree.
Evidence considered
pvs1_variant_assessment.json: consequence_class='unknown', variant_bucket='other', apply_generic_pvs1_framework=false, rationale='This variant does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical +/-1,2 splice consensus variants.'
gnomAD-Canada VEP annotation: most_severe_consequence='3_prime_UTR_variant', variant_class='SNV' for 17-31374159-T-C (GRCh38), confirming the variant lies in the 3' UTR downstream of the NF1 stop codon rather than in coding sequence.
pvs1_gene_context.json confirms NF1 loss-of-function is an established germline disease mechanism (lof_mechanism_supported=true), which establishes PVS1 gene-level eligibility in principle, but does not change the variant-level conclusion that this specific 3'UTR SNV is not a null-variant class recognized by the PVS1 decision tree.
NF1 CSPEC (ClinGen Neurofibromatosis and Schwannomatosis EP v1.0) rule_payload contains no structured, gene-specific PVS1 override for UTR variants; generic ACMG/SVI PVS1 framework (PMC6185798) applied as fallback per case pvs1_variant_assessment framework_source.
PS1N/ANot applicable: the variant produces no amino acid change, so no comparison to an established pathogenic change at the same residue is possible.
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Reasoning
NM_001042492.2:c.*4T>C is a 3' UTR variant (position denoted by the '*' offset downstream of the stop codon). It does not alter any codon or amino acid; protein consequence is annotated as NP_001035957.1:p.? with no variant_class assigned. PS1 requires establishing that the variant produces the same amino acid change as a previously established pathogenic variant at that residue, which is not applicable to a non-coding 3' UTR change.
Evidence considered
case_summary.json compact_evidence.normalization shows protein_3l/protein_1l = 'NP_001035957.1:p.?' and variant_class = null, confirming c.*4T>C lies in the 3' UTR downstream of the stop codon and does not encode an amino acid substitution.
Still missing
No protein-level change exists for this variant; PS1 concept does not apply.
PM1N/ANot applicable: with no amino acid change, there is no residue or domain location to evaluate.
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Reasoning
PM1 assesses missense variant location in a mutational hotspot or well-characterized functional domain. NM_001042492.2:c.*4T>C is a 3' UTR variant with no amino acid change, so there is no residue or domain location to evaluate.
Evidence considered
case_summary.json compact_evidence.normalization confirms no protein change (p.?) for this 3' UTR variant.
Still missing
No codon/residue exists for this variant; PM1 domain/hotspot analysis is not applicable.
PM3N/ANot applicable: NF1 is autosomal dominant, so the recessive-disease allelic criterion does not apply.
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Reasoning
The governing NF1 specification identifies neurofibromatosis type 1 as autosomal dominant. PM3 is a recessive-disease allelic criterion, and no affected-proband observation of this variant in trans with a pathogenic NF1 variant is provided.
Rule
Generic ACMG/AMP PM3 is not applicable to the specified autosomal-dominant NF1 disease context.
Evidence considered
The NF1 ClinGen Neurofibromatosis and Schwannomatosis Expert Panel framework specifies neurofibromatosis type 1 with autosomal dominant inheritance.
The consolidated case evidence contains no affected-proband genotype with a second NF1 variant and no phase evidence in trans.
PM4N/ANot applicable: no codon is deleted, inserted, or altered, so protein length is unchanged.
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Reasoning
PM4 applies to in-frame deletions/insertions or stop-loss variants that change protein length. NM_001042492.2:c.*4T>C is a 3' UTR single-nucleotide substitution located downstream of the stop codon; it does not delete, insert, or otherwise alter any codon, and predicted protein annotation is NP_001035957.1:p.? (no amino-acid-level consequence). There is no stop-loss (the variant is 4 nt 3' of the termination codon, not at or altering it) and no in-frame indel of any kind. No gene-specific NF1 CSPEC guidance modifies PM4 for UTR variants. Protein length is therefore unchanged, so PM4 cannot be met.
Rule
PM4 not applicable: variant does not alter protein length (no in-frame indel, no stop-loss); it is a non-coding 3' UTR substitution with no predicted amino-acid change.
Evidence considered
pvs1_variant_assessment.json: protein_1l/protein_3l = 'NP_001035957.1:p.?', consequence_class='unknown', confirming no predicted protein-level change for this variant.
gnomAD-Canada VEP annotation: most_severe_consequence='3_prime_UTR_variant', variant_class='SNV', confirming the substitution is downstream of the stop codon and not a coding, stop-loss, or indel event.
NF1 CSPEC rule_payload contains no gene-specific PM4 modification applicable to UTR variants.
PM5N/ANot applicable: no amino acid substitution occurs, so there is no residue to compare with known pathogenic changes.
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Reasoning
PM5 requires a different amino acid change at the same residue previously classified as pathogenic. Since c.*4T>C is a 3' UTR variant producing no amino acid substitution, there is no residue at which to compare alternate missense changes.
Evidence considered
case_summary.json compact_evidence.normalization confirms no protein change (p.?) for this 3' UTR variant.
Still missing
No residue/codon exists for this variant; PM5 is not applicable.
PP2N/ANot applicable: the criterion applies to missense variants, not 3' UTR changes.
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Reasoning
PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common mechanism of pathogenicity. c.*4T>C is a 3' UTR variant, not a missense variant, so PP2's missense-constraint logic does not apply regardless of NF1's missense tolerance profile.
Evidence considered
case_summary.json compact_evidence.normalization confirms no protein change (p.?) for this 3' UTR variant.
Still missing
Variant is not missense; PP2 gene-level missense constraint criterion is not applicable.
BS1N/ANot applicable: already covered by the met BA1 population-frequency criterion, so it is not stacked.
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Reasoning
BA1 is met; BS1 is redundant and must not be stacked with BA1 for the same population-frequency evidence.
Rule
Do not combine redundant BA1 and BS1 evidence from the same population-frequency observation
Evidence considered
The v4.1 South Asian grpmax FAF is 1.8399%, supporting BA1-level frequency evidence rather than a separate BS1 application.
BP1N/ANot applicable: the criterion applies to missense variants, not 3' UTR changes.
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Reasoning
BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism (missense variants are generally benign). c.*4T>C is a 3' UTR variant, not a missense variant, so BP1 does not apply.
Evidence considered
case_summary.json compact_evidence.normalization confirms no protein change (p.?) for this 3' UTR variant.
Still missing
Variant is not missense; BP1 gene-level missense-benign criterion is not applicable.
BP3N/ANot applicable: the criterion requires an in-frame deletion or insertion, not a single-nucleotide substitution.
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Reasoning
BP3 applies to in-frame deletions/insertions in a repetitive region without a known function. NM_001042492.2:c.*4T>C is a single-nucleotide substitution in the 3' UTR, not an in-frame indel, so the criterion's variant-type precondition is not met regardless of repeat-region context. No NF1 CSPEC-specific BP3 modification changes this precondition.
Rule
BP3 not applicable: variant is a non-coding 3' UTR SNV, not an in-frame insertion/deletion, so the criterion's structural precondition is not satisfied.
Evidence considered
gnomAD-Canada VEP annotation: most_severe_consequence='3_prime_UTR_variant', variant_class='SNV', confirming this is a substitution, not an in-frame insertion/deletion, so BP3's structural precondition (in-frame indel in a non-critical/repetitive region) is not met.
pvs1_variant_assessment.json confirms no protein-level consequence (p.?) consistent with a non-coding UTR substitution rather than an in-frame indel.
NF1 CSPEC rule_payload contains no gene-specific BP3 modification applicable here.
BP7N/ANot applicable: the variant is a 3' UTR change outside the coding sequence, not a synonymous coding variant.
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Reasoning
BP7 applies to synonymous (silent) coding variants with no predicted splicing effect. NM_001042492.2:c.*4T>C is a 3' UTR variant located outside the coding sequence and does not alter any codon, so it is not a synonymous variant and BP7 is not applicable. The splice-impact assessment for this variant (no predicted effect via SpliceAI) is captured under BP4 instead.
Evidence considered
Variant NM_001042492.2:c.*4T>C is annotated as a 3' UTR substitution (case_summary.json protein_3l = 'NP_001035957.1:p.?', no coding/synonymous consequence), so the synonymous-variant criterion BP7 does not apply.
Identifiers
Gene
NF1
Transcript
NM_001042492.2
Coding (HGVS c.)
NM_001042492.2:c.*4T>C
Protein (HGVS p.)
NP_001035957.1:p.?
GRCh38
chr17:31374159 T>C
GRCh37
chr17:29701177 T>C
Location and type
Exon 58 · unknown
ClinVar
184532
Gene diagram
Every interpreted variant in NF1, mapped onto the exon structure of NM_001042492.2. Select a row to find it on the plot.
NF1NM_001042492.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in NF1—Select a row to find it on the plot; use the link to open its page.
AF 0.0011 · 1847 / 1,613,986 alleles · 22 hom · FAF 0.018
South Asian1744 / 91,084
0.01922 hom
Remaining individuals88 / 62,502
0.0014
Middle Eastern3 / 6,056
0.0005
African/African American7 / 75,018
9.3e-05
East Asian2 / 44,876
4.5e-05
European (non-Finnish)3 / 1,179,914
2.5e-06
0 alternate alleles recorded in 4 other groups: Admixed American, European (Finnish), Amish, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0022 · 630 / 282,758 alleles · 6 hom · FAF 0.019
South Asian616 / 30,612
0.026 hom
Remaining individuals10 / 7,224
0.0014
African/African American2 / 24,956
8e-05
East Asian1 / 19,948
5e-05
European (non-Finnish)1 / 129,132
7.7e-06
0 alternate alleles recorded in 3 other groups: Admixed American, Ashkenazi Jewish, European (Finnish).
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00114437; MAF= 0.11444%, 1847/1613986 alleles, homozygotes = 22) and has highest observed frequency in the South Asian population (AF= 0.0191472; MAF= 1.91472%, 1744/91084 alleles, homozygotes = 22); grpmax FAF= 0.0183991.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00222805; MAF= 0.22281%, 630/282758 alleles, homozygotes = 6) and has highest observed frequency in the South Asian population (AF= 0.0201228; MAF= 2.01228%, 616/30612 alleles, homozygotes = 6); grpmax FAF= 0.0188075.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.001954185213331886, 36/18422 alleles, homozygotes = 0).
BP4SupportingMet (supporting): SpliceAI predicts no splice impact, with max delta score 0.004, consistent with a benign effect.
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Reasoning
SpliceAI predicts no meaningful splice impact for NM_001042492.2:c.*4T>C (max delta score 0.004, all four delta scores <=0.004), well below the calibrated donor/acceptor gain-or-loss threshold used to flag possible splice disruption. This is a 3' UTR variant with no missense consequence, so no missense in-silico prediction path applies. The computational evidence is consistent with a benign impact, supporting BP4 at supporting strength.
Evidence considered
SpliceAI Lookup: DS_AG=0.00, DS_AL=0.001, DS_DG=0.00, DS_DL=0.004, max delta=0.004 for NM_001042492.2:c.*4T>C, indicating no predicted disruption of splice donor/acceptor sites.
Variant lies in the 3' UTR, 4 nt beyond the stop codon; no missense change is created, so REVEL/BayesDel/aGVGD computational missense evidence does not apply here.
PP3Not met: SpliceAI max delta 0.004, far below the ~0.2 threshold used to flag splice impact.
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Reasoning
NM_001042492.2:c.*4T>C is a 3' UTR variant (4 bp downstream of the stop codon), not a missense or splice-region substitution near a canonical consensus site. SpliceAI (the applicable computational tool for this variant type) predicts no splice impact: max delta score 0.004 (DS_AG 0.00, DS_AL 0.001, DS_DG 0.00, DS_DL 0.004), far below any calibrated pathogenic threshold (typically >=0.2). No missense in-silico predictors (REVEL/BayesDel/aGVGD) apply since this is not a missense variant. No NF1 VCEP gene-specific PP3/BP4 lookup table was found in vcep_materials for this position. PP3 is not met.
Evidence considered
SpliceAI Lookup for NM_001042492.2:c.*4T>C: DS_AG=0.00, DS_AL=0.001, DS_DG=0.00, DS_DL=0.004, max delta score=0.004 (all scores near zero, far below the 0.2 pathogenic-supporting threshold commonly used for PP3 splice application).
Variant is located in the 3' UTR (c.*4 position), not a missense change, so REVEL/BayesDel/aGVGD missense predictors are not applicable to this variant type.
No NF1 ClinGen VCEP gene-specific PP3/BP4 lookup spreadsheet was present in vcep_materials.json for this case; framework note only references the general NF1 cspec ruleset with no rule_payload content.
BP7N/ANot applicable: the variant is a 3' UTR change outside the coding sequence, not a synonymous coding variant.
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Reasoning
BP7 applies to synonymous (silent) coding variants with no predicted splicing effect. NM_001042492.2:c.*4T>C is a 3' UTR variant located outside the coding sequence and does not alter any codon, so it is not a synonymous variant and BP7 is not applicable. The splice-impact assessment for this variant (no predicted effect via SpliceAI) is captured under BP4 instead.
Evidence considered
Variant NM_001042492.2:c.*4T>C is annotated as a 3' UTR substitution (case_summary.json protein_3l = 'NP_001035957.1:p.?', no coding/synonymous consequence), so the synonymous-variant criterion BP7 does not apply.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
11 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia.
Boudry-Labis E et al. · 2013
This study screened 488 previously untreated de novo AML patients for somatic NF1 deletions and sequenced NF1 in a 20-patient subset. It does not report NM_001042492.2:c.*4T>C as an affected-case variant or provide a case-control association for it.
We screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches.
Abstract, lines 8-21 of the supplied full text
A systematic approach to assessing the clinical significance of genetic variants.
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.
This study investigates the interaction of Nf1 and Gmcsf in murine myeloid leukemogenesis. It supports neither an observation of the exact human NF1 c.*4T>C variant nor case-control enrichment for that variant.
Children with NF1 are predisposed to juvenile myelomonocytic leukemia (JMML). Some heterozygous Nf1 mutant mice develop a similar myeloproliferative disorder (MPD).
Summary, lines 46-61 of the supplied full text
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
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.
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= 0.00114437; MAF= 0.11444%, 1847/1613986 alleles, homozygotes = 22) and has highest observed frequency in the South Asian population (AF= 0.0191472; MAF= 1.91472%, 1744/91084 alleles, homozygotes = 22); grpmax FAF= 0.0183991.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00222805; MAF= 0.22281%, 630/282758 alleles, homozygotes = 6) and has highest observed frequency in the South Asian population (AF= 0.0201228; MAF= 2.01228%, 616/30612 alleles, homozygotes = 6); grpmax FAF= 0.0188075.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.001954185213331886, 36/18422 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Benign (10 clinical laboratories) and as Likely benign (6 clinical laboratories). (ClinVarID = 184532)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
This variant was interpreted by pipeline 7.1.5.
The current version is 11.0.07.
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