NF1 c.1806A>G, p.(Glu602=)

Reasoning

BP7 is met at supporting strength for this synonymous variant because NM_001042492.2:c.1806A>G (p.Glu602=) does not change the encoded amino acid and SpliceAI reports a maximum delta score of 0.078, below the supplied no-significant-splice-impact cutoff of 0.1. The result is based on the SpliceAI path only and is not double-counted with PP3 or BP4, which are out of scope here. The generic SpliceAI calibration is used because the NF1 specification contains no extracted BP7-specific rule.

Rule

Generic ACMG/AMP BP7: synonymous variant with no predicted splice impact; SpliceAI maximum delta <=0.1 supports the no-significant-splice-impact component.

Evidence considered

• The case variant is synonymous: NM_001042492.2:c.1806A>G, NP_001035957.1:p.(Glu602=).
• SpliceAI reports DS_AG 0.078, DS_DG 0.047, DS_AL 0.0, DS_DL 0.0, with maximum delta score 0.078.
• The supplied generic SpliceAI calibration defines <=0.1 as the recommended no-significant-splice-impact threshold for benign computational evidence; this calibration is attributed to Jaganathan et al. 2019 (PMID:30661751).
• The NF1 ClinGen specification is governing but has no extracted criterion-specific BP7 rule, so the supplied generic calibration is used.

Sources

Reasoning

The NF1 framework contains no usable PM2-specific population rule, so the supplied generic SVI PM2 supporting threshold of AF <= 0.0001 applies. Aggregate frequencies are below the cutoff: AF 4.22969e-05 in gnomAD v2.1 non-cancer exomes, 3.37925e-05 in gnomAD v3.1 non-cancer genomes, 4.25029e-05 in combined gnomAD v2.1, and 3.59625e-05 in combined gnomAD v4.1. However, the highest ancestry-specific frequency is 1.01764e-04 in the gnomAD v2.1 non-cancer European (non-Finnish) subgroup, which is above the strict 0.0001 cutoff; therefore PM2 is not met despite zero homozygotes in all reported datasets.

Rule

Generic PM2 supporting requires AF <= 0.0001 across the relevant population; the NF1 framework supplied no usable PM2-specific rule.

Evidence considered

• The NF1 VCEP/CSPEC record is available, but its extracted rule payload contains no usable PM2-specific rule, so the supplied generic SVI PM2 supporting threshold of AF <= 0.0001 was used across ancestry-specific populations.
• gnomAD v2.1 non-cancer exomes report AF 4.22969e-05 from 10/236424 alleles with zero homozygotes; gnomAD v3.1 non-cancer genomes report AF 3.37925e-05 from 5/147962 alleles with zero homozygotes.
• Combined gnomAD v2.1 reports AF 4.25029e-05 from 12/282334 alleles and combined gnomAD v4.1 reports AF 3.59625e-05 from 58/1612792 alleles; both report zero homozygotes. The gnomAD v2.1 non-cancer European (non-Finnish) subgroup reaches AF 1.01764e-04, exceeding the strict PM2 cutoff.

Sources

Reasoning

The exact-variant ClinVar record for NM_001042492.3(NF1):c.1806A>G (p.Glu602=) has zero expert-panel submissions. Its Likely benign and Benign assertions are from ordinary single-submitter clinical laboratories or other non-expert submissions, and the aggregate ClinVar record is conflicting. Under the required rule, no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification exists to support PP5.

Rule

PP5 is met only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• The exact-variant ClinVar audit reports 0 expert-panel submissions.
• The available exact-variant classifications are non-expert single-submitter assertions: four Likely benign, one Benign, and one Uncertain significance submission summary.
• Ordinary laboratory submissions and aggregate ClinVar labels are excluded from PP5 by the governing adjudication rule.

Sources

Reasoning

The governing NF1 specification is present but contains no usable criterion-specific population rules, so the supplied generic ACMG/AMP BA1 threshold applies. The variant is far below the stand-alone benign threshold of AF >= 0.05: AF is 4.22969e-05 in gnomAD v2.1 non-cancer exomes, 3.37925e-05 in gnomAD v3.1 non-cancer genomes, 4.25029e-05 in combined gnomAD v2.1, and 3.59625e-05 in combined gnomAD v4.1. The highest reported subgroup AF is 1.01764e-04 in the gnomAD v2.1 non-cancer European (non-Finnish) subgroup, still well below 0.05; therefore BA1 is not met.

Rule

Generic BA1: AF >= 0.05 is stand-alone benign; the NF1 framework supplied no usable BA1-specific rule.

Evidence considered

• The NF1 VCEP/CSPEC record is available, but its extracted rule payload contains no usable BA1 threshold, so the supplied generic ACMG/AMP threshold of AF >= 0.05 was used.
• gnomAD v2.1 non-cancer exomes report 10/236424 alleles, AF 4.22969e-05, with zero homozygotes; its highest subgroup AF is 1.01764e-04 in European (non-Finnish) individuals.
• gnomAD v3.1 non-cancer genomes report 5/147962 alleles, AF 3.37925e-05, with zero homozygotes; combined gnomAD v4.1 reports AF 3.59625e-05 with zero homozygotes.

Sources

Reasoning

The governing NF1 specification contains no usable BS1 population rule, so the supplied generic BS1 threshold applies. All available population estimates are below AF >= 0.01: 4.22969e-05 in gnomAD v2.1 non-cancer exomes, 3.37925e-05 in gnomAD v3.1 non-cancer genomes, 4.25029e-05 in combined gnomAD v2.1, and 3.59625e-05 in combined gnomAD v4.1. The highest reported subgroup AF, 1.01764e-04 in the gnomAD v2.1 non-cancer European (non-Finnish) subgroup, is also below 0.01; therefore BS1 is not met.

Rule

Generic BS1: AF >= 0.01 is strong benign population evidence; the NF1 framework supplied no usable BS1-specific rule.

Evidence considered

• The NF1 VCEP/CSPEC record is available, but its extracted rule payload contains no usable BS1-specific threshold, so the supplied generic threshold of AF >= 0.01 was used.
• The relevant non-cancer estimates are AF 4.22969e-05 in gnomAD v2.1 exomes and AF 3.37925e-05 in gnomAD v3.1 genomes; combined all-comers estimates are AF 4.25029e-05 in gnomAD v2.1 and AF 3.59625e-05 in gnomAD v4.1.

Sources

Reasoning

The exact-variant ClinVar record for NM_001042492.3(NF1):c.1806A>G (p.Glu602=) has zero expert-panel submissions. Its Likely benign and Benign classifications are ordinary single-submitter laboratory assertions, while the aggregate record is conflicting; therefore no exact-variant ClinVar expert-panel Benign or Likely benign classification exists to support BP6.

Rule

BP6 is met only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; ordinary laboratory submissions and aggregate labels do not qualify.

Evidence considered

• The exact-variant ClinVar audit reports 0 expert-panel submissions.
• The available Benign and Likely benign classifications are from non-expert single-submitter laboratory submissions.
• The aggregate ClinVar label is not eligible for BP6 under the required expert-panel-only rule.

Sources

Reasoning

The NF1-specific framework is present but contains no criterion-level rules for PS2. The available case evidence documents the synonymous variant NM_001042492.2:c.1806A>G (p.Glu602=), but provides no proband-level de novo observation, confirmed maternity and paternity, parental genotypes, or exclusion of parental mosaicism. The de novo-themed papers reviewed do not mention this exact variant and therefore cannot establish PS2.

Evidence considered

• The NF1 ClinGen specification is available, but its retrieved rule payload contains no criterion-level PS2 rule.
• The case materials identify NM_001042492.2:c.1806A>G as a synonymous NF1 variant (p.Glu602=) but report no parental genotypes or de novo testing.
• PMID:23460398 evaluated de novo AML patients but its extracted finding states that silent NF1 mutations were excluded and the exact c.1806A>G variant was not mentioned.
• PMID:29872168 reports somatic NF1 mutations in de novo AML but does not mention this exact synonymous variant or provide family-based de novo evidence.

Still missing

• Documented proband phenotype and diagnostic context
• Confirmed maternity and paternity
• Parental testing results for NM_001042492.2:c.1806A>G
• Assessment for parental mosaicism

Sources

Reasoning

PS3 cannot be assessed because no validated functional study directly tests NF1 NM_001042492.2:c.1806A>G (p.Glu602=). The reviewed exact-variant literature either excludes silent NF1 mutations or reports unrelated NF1 variants and does not provide an RNA, protein, cellular, or other assay result for c.1806A>G. The NF1 VCEP specification is present but contains no criterion-specific PS3 rule or assay calibration in the supplied materials. SpliceAI's computational prediction (maximum delta 0.078) is not functional evidence and cannot substitute for a validated assay.

Evidence considered

• The NF1 VCEP specification (version 1.0) is the governing framework, but the supplied specification has no PS3 criterion-specific rule or functional-assay calibration.
• PMID:10678181 describes experiments in Nf1-deficient murine hematopoietic cells, but the exact human variant c.1806A>G is not mentioned and the experiments do not test this variant.
• PMID:23460398 reports that silent NF1 mutations were excluded from retained AML variants; it does not test or report c.1806A>G.
• PMID:29872168 reports somatic NF1 nonsense, frameshift, missense, and in-frame variants in AML, but does not report or functionally test c.1806A>G.
• SpliceAI predicts a maximum delta score of 0.078, but this computational result is not a validated functional assay and cannot establish PS3.

Still missing

• A validated assay directly testing NF1 c.1806A>G is unavailable, including appropriate positive and negative controls.
• No variant-specific measurement of transcript, splicing, neurofibromin expression, Ras-GAP activity, or cellular phenotype is available.

Sources

Reasoning

The NF1 ClinGen specification was identified, but its retrieved criterion payload is empty and supplies no PS4-specific rule. The available evidence contains no exact-variant affected-case series, case-control comparison, odds ratio, or other statistically enriched phenotype observation for NM_001042492.2:c.1806A>G. The reviewed exact-variant-linked papers either do not mention this variant or explicitly report that silent NF1 mutations were excluded; therefore PS4 cannot be assessed from the available evidence.

Rule

Generic PS4 requires statistically significant enrichment of the variant in affected individuals compared with an appropriate control population; no exact-variant threshold or enrichment statistic is available here.

Evidence considered

• The NF1 ClinGen specification is present, but no criterion-specific rules were retrieved in its payload.
• PMID:10678181 reports murine Nf1-deficient myeloid disease and does not mention the exact variant.
• PMID:23460398 reports that silent NF1 mutations were excluded from its de novo AML analysis and does not mention the exact variant.
• PMID:29872168 reports somatic NF1 mutations in AML but does not mention the exact synonymous variant or provide variant-specific case-control evidence.

Still missing

• An exact-variant affected-case series or case-control study with a defined phenotype and statistical enrichment measure is needed.
• A PS4-specific NF1 VCEP rule was not retrieved; the CSPEC criterion payload is empty.

Sources

Reasoning

The NF1-specific framework is present but contains no criterion-level rules for PM6. No case report or literature source documents this exact variant in an apparently de novo affected individual without parental testing. The reviewed de novo AML papers concern somatic or other NF1 mutations and do not establish PM6 for NM_001042492.2:c.1806A>G.

Evidence considered

• The NF1 ClinGen specification is available, but its retrieved rule payload contains no criterion-level PM6 rule.
• No source in the case materials reports NM_001042492.2:c.1806A>G in an affected individual as apparently de novo.
• PMID:23460398 and PMID:29872168 discuss other NF1 alterations in de novo AML contexts, but neither mentions the exact synonymous variant or supports PM6.

Still missing

• A documented affected individual carrying the exact variant
• Evidence supporting an apparently de novo occurrence
• Clarification of whether parental testing was performed

Sources

Reasoning

The NF1-specific framework is present but contains no criterion-level rules for PP1. The available evidence contains no affected relatives, informative meioses, family pedigree, segregation counts, or genotype-phenotype co-segregation data for NM_001042492.2:c.1806A>G. Literature reviewed for this group does not report this exact variant in a familial segregation study.

Evidence considered

• The NF1 ClinGen specification is available, but its retrieved rule payload contains no criterion-level PP1 rule.
• The case materials provide no family pedigree, affected-relative genotypes, informative meioses, or segregation observations for NM_001042492.2:c.1806A>G.
• The reviewed NF1 literature sources do not mention this exact variant in a familial segregation analysis.

Still missing

• Family pedigree and phenotype information
• Genotypes and phenotypes of informative relatives
• Number of informative meioses
• Variant co-segregation results

Sources

Reasoning

The NF1 ClinGen specification was identified, but its retrieved criterion payload is empty and supplies no PP4-specific rule. The case materials provide variant normalization and molecular evidence but no proband phenotype, clinical diagnosis, or highly specific NF1 phenotype. General NF1 disease descriptions in background literature are not sufficient to establish PP4 for this individual variant, so PP4 cannot be assessed.

Rule

Generic PP4 requires the patient's phenotype or highly specific disease features to be highly specific for the disorder; no patient phenotype is available.

Evidence considered

• The case materials do not document a proband phenotype or clinical diagnosis that can be compared with NF1-specific features.
• General gene-level NF1 descriptions do not establish phenotype specificity for this individual variant.

Still missing

• The individual's phenotype and clinical diagnosis are needed.
• A PP4-specific NF1 VCEP rule was not retrieved; the CSPEC criterion payload is empty.

Sources

Reasoning

The variant is observed in population databases, but the available gnomAD records provide allele counts and zero homozygotes rather than documented unaffected adult carriers with phenotype assessment. Because NF1 is autosomal dominant and no clinically characterized healthy carriers or disease-specific penetrance analysis is supplied, the population data alone cannot establish BS2; BS2 is not assessed.

Rule

BS2 requires variant observation in healthy adults for a dominant condition, or in healthy individuals homozygous for a recessive condition; population allele counts without phenotype ascertainment are insufficient.

Evidence considered

• gnomAD v2.1 non-cancer exomes contain 10 alternate alleles and zero homozygotes; gnomAD v3.1 non-cancer genomes contain 5 alternate alleles and zero homozygotes.
• Combined gnomAD v2.1 and v4.1 contain 12 and 58 alternate alleles, respectively, with zero homozygotes, but these records do not establish that carriers are unaffected adults or provide NF1 penetrance ascertainment.

Still missing

• No documented unaffected adult carriers with adequate NF1 phenotype assessment or penetrance context.

Sources

Reasoning

BS3 cannot be assessed because no validated functional study directly demonstrates a normal effect of NF1 NM_001042492.2:c.1806A>G (p.Glu602=). The available papers do not test this exact synonymous variant; general observations about synonymous variants and the absence of a predicted splice effect do not establish normal function. SpliceAI's maximum delta score of 0.078 is computational evidence only and is not sufficient for BS3.

Evidence considered

• The NF1 VCEP specification (version 1.0) is the governing framework, but the supplied specification has no BS3 criterion-specific rule or functional-assay calibration.
• PMID:26467025 reports broad laboratory classification trends in which many synonymous variants were benign, but it does not mention NF1 c.1806A>G and provides no variant-specific functional result.
• PMID:23460398 and PMID:29872168 do not report or assay the exact synonymous variant c.1806A>G.
• SpliceAI predicts a maximum delta score of 0.078, but absence of a computational splice signal is not validated evidence of normal function and cannot establish BS3.

Still missing

• A variant-specific functional assay with suitable normal and disease-control comparators is unavailable.
• No direct evidence confirms normal RNA splicing, neurofibromin expression, Ras-GAP activity, or cellular function for this variant.

Sources

Reasoning

The NF1-specific framework is present but contains no criterion-level rules for BS4. No unaffected relatives with reliable age-appropriate clinical assessment and confirmed carriage of NM_001042492.2:c.1806A>G are documented. Absence of family data cannot establish non-segregation.

Evidence considered

• The NF1 ClinGen specification is available, but its retrieved rule payload contains no criterion-level BS4 rule.
• The case materials contain no confirmed variant-positive unaffected relatives or reliable age-appropriate phenotype assessments for this family.
• No non-segregation observation is reported; missing family information cannot be treated as evidence for BS4.

Still missing

• Confirmed variant-positive unaffected relatives
• Reliable age-appropriate clinical assessment
• Relevant family segregation and phenotype data

Sources

Reasoning

BP2 requires documented co-occurrence of the variant with a pathogenic variant in the same affected individual, with phase information showing the relevant relationship. The available case evidence contains no affected-proband observation, second pathogenic variant, cis/trans determination, or family segregation result for NM_001042492.2:c.1806A>G; therefore BP2 cannot be assessed.

Rule

BP2 requires variant-specific co-occurrence with a pathogenic variant in the same individual and appropriate phase information; neither is documented here.

Evidence considered

• The case evidence documents the synonymous NF1 variant NM_001042492.2:c.1806A>G (p.Glu602=) but provides no affected individual with a second pathogenic variant.
• No cis/trans phase result or segregation study is available for evaluating BP2.

Still missing

• Affected-proband observations with a second pathogenic variant are not documented.
• Cis/trans phase information is not documented.
• Family segregation or inheritance data relevant to co-occurrence are not documented.

Reasoning

The NF1 ClinGen specification was identified, but its retrieved criterion payload is empty and supplies no BP5-specific rule. The available materials do not document an affected individual with this exact variant and a separate established pathogenic variant explaining the phenotype, nor do they provide a BP5 likelihood-ratio-style statistic or governing threshold. Population observations and non-expert ClinVar benign assertions cannot establish BP5.

Rule

BP5 requires evidence that an alternative pathogenic variant explains the patient's phenotype; no applicable NF1-specific rule, qualifying patient-level evidence, or numeric threshold is available.

Evidence considered

• No patient-level co-occurrence or alternative pathogenic diagnosis is present in the available case evidence.
• The NF1 CSPEC criterion payload is empty, so no gene-specific BP5 rule or numeric threshold is available.
• The ClinVar record contains only non-expert assertions and cannot substitute for individual-level BP5 evidence.

Still missing

• An affected individual-level co-occurrence record with an alternative pathogenic explanation is needed.
• A BP5-specific NF1 rule and any governing numeric operator or threshold were not retrieved.

Sources