NM_001042492.2:c.3479G>A

NF1 · NP_001035957.1:p.(Gly1160Asp) · NM_001042492.2

GRCh37: chr17:29559882 G>A · GRCh38: chr17:31232864 G>A

Gene: NF1 Transcript: NM_001042492.2

Final call

VUS

PM2 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.(Gly1160Asp)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001042492.2:c.3479G>A (p.Gly1160Asp) in NF1 is a missense variant absent from gnomAD population databases (v2.1, v4.1, Canada v1.0), satisfying PM2 at supporting strength.

This variant does not meet PVS1 criteria, as it is a missense variant and does not fall into the null-variant buckets (nonsense, frameshift, canonical splice) defined by the ClinGen SVI PVS1 recommendations (PMC6185798).

No variant-specific functional studies (PS3/BS3), segregation data (PP1/BS4), de novo observations (PS2/PM6), case-control prevalence (PS4), or same-residue pathogenic comparators (PM5/PS1) were identified in ClinVar or the literature.

In silico predictions are conflicting: REVEL (0.851) supports a deleterious effect while BayesDel (0.15882) is in the benign range, and SpliceAI predicts no splice impact (max delta 0.06). These conflicting results preclude application of both PP3 and BP4.

ClinVar classification is Likely pathogenic with review status 'criteria provided, single submitter' (2★); conflicting submissions exist (2 LP, 2 VUS, 1 P). PP5 does not apply at this review level and BP6 is not met as no benign classification exists.

The NF1 CSPEC framework (ClinGen Neurofibromatosis and Schwannomatosis Expert Panel, Version 1.0) was retrieved but is incomplete (framework_complete=false, empty criteria). Generic ACMG/AMP 2015 combination rules (PMID:25741868) are applied for final classification.

With only one supporting pathogenic criterion (PM2) met and no benign criteria, this variant does not reach the threshold for Likely Pathogenic or Likely Benign classification under generic ACMG/AMP 2015 rules. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (p.Gly1160Asp), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). Does not fall into the default generic PVS1 null-variant buckets per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence of a different nucleotide change at the same codon resulting in the same amino acid substitution that has been established as pathogenic. Neither the ClinVar records nor the literature identify a same-amino-acid PS1 comparator for p.Gly1160Asp.	clinvar pm5_candidates
PS2	Not met	No de novo observation confirmed for NM_001042492.2:c.3479G>A. No paper in the case folder reports a de novo finding with confirmed maternity and paternity for this variant.
PS3	Not met	No variant-specific functional data identified for p.Gly1160Asp. OncoKB classifies this variant as 'Unknown Oncogenic Effect'. No published functional studies in the literature packet directly test this variant or a systematically characterized range that includes position 1160.	oncokb
PS4	Not met	No case-control prevalence data available. While this variant has been reported to ClinVar in multiple clinical testing submissions, no peer-reviewed publication provides variant-specific prevalence data in affected versus control populations. The ClinVar criterion-lead papers are guidelines or consensus statements that do not provide variant-specific case observations.	clinvar
PS5	Not met	No expert panel classification of this variant as pathogenic in ClinVar. The ClinVar review status is 'criteria provided, single submitter' (2★). A 3★ expert panel classification is required for PS5 application.	clinvar
PM1	Not met	This variant (p.Gly1160Asp) is not located in a statistically significant mutational hotspot per cancerhotspots.org. Position 1160 falls within the tubulin-binding domain (TBD/pre-GRD region) of neurofibromin, but no literature in the case folder specifically establishes this residue or domain as a critical functional domain satisfying PM1 under the NF1 CSPEC framework or generic ACMG/AMP criteria.	pvs1_gene_context
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant. Under generic ACMG/AMP 2015, absence from large population cohorts supports PM2 at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 applies to recessive disorders (variant detected in trans with a pathogenic variant). NF1 is an autosomal dominant disorder.
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. This is a missense substitution.
PM5	Not met	No confirmed pathogenic variant at the same amino acid position (Gly1160) with a different amino acid change was identified. The automated PM5 candidate harvest failed to find same-residue comparator variants in ClinVar.	pm5_candidates clinvar
PM6	Not met	No de novo observation with unconfirmed maternity/paternity reported for this variant. PM6 requires at least one de novo finding where both parents are not confirmed.
PP1	Not met	No segregation data available for this variant. PP1 requires co-segregation of the variant with disease in multiple affected family members.
PP2	Not met	Insufficient data to determine if NF1 has a low rate of benign missense variation. The HCI prior was not available for this variant, and no gene-level missense constraint score was retrieved to satisfy generic ACMG/AMP PP2 requirements.
PP3	Not met	In silico predictions are conflicting. REVEL score of 0.851 predicts a deleterious effect, but BayesDel score of 0.159 is in the benign range. SpliceAI predicts no splice impact (max delta 0.06). Under generic ACMG/AMP, PP3 requires multiple lines of computational evidence uniformly supporting a deleterious effect, which is not satisfied by these conflicting results.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data available to assess whether the clinical presentation is highly specific for NF1 (neurofibromatosis type 1). PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar review status for this variant is 'criteria provided, single submitter' (2★). Per adjudication rules, PP5 applies at supporting strength only when a 3★ expert panel classification is present. The CSPEC framework does not override this threshold.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires allele frequency >5% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires allele frequency greater than expected for the disorder (>0.3% non-VCEP). This variant is absent from all population databases, so BS1 is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No evidence that this variant has been observed in a healthy adult individual in trans with a known pathogenic dominant variant. BS2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BS3	Not met	No well-established functional studies demonstrate no deleterious effect of this variant. OncoKB classifies this variant as 'Unknown Oncogenic Effect', and no published functional assays were identified in the literature packet.	oncokb
BS4	Not met	No family segregation data available. BS4 requires lack of segregation of the variant with disease in affected family members.
BP1	Not met	NF1 is not a gene where only truncating variants cause disease; missense variants are a well-established pathogenic mechanism in NF1. BP1 requires the variant class (missense) in a gene where primarily truncating variants cause disease.	pvs1_gene_context
BP2	Not met	No evidence that this variant is observed in trans with a known pathogenic variant for a fully penetrant dominant disorder. No co-occurrence or phasing data available.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions with unknown function. This is a substitution variant.
BP4	Not met	Multiple lines of computational evidence do NOT uniformly suggest no impact. REVEL score of 0.851 supports a deleterious effect, contradicting any benign computational assessment. BP4 requires multiple lines of evidence suggesting no impact on gene product.	revel bayesdel spliceai
BP5	Not met	No evidence that this variant is found in a case with an established alternative molecular basis for disease. BP5 requires observation in a case with a known pathogenic variant in an alternative gene that explains the phenotype.
BP6	Not met	ClinVar does not classify this variant as benign or likely benign. The ClinVar classification is Likely pathogenic with conflicting submissions (2 LP, 2 VUS, 1 P). BP6 would require a reputable source classifying as benign at 3★ review level.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a missense variant (p.Gly1160Asp), not synonymous.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.