NM_001042492.2:c.6776T>C

NF1 · NP_001035957.1:p.(Val2259Ala) · NM_001042492.2

GRCh37: chr17:29665114 T>C · GRCh38: chr17:31338096 T>C

Gene: NF1 Transcript: NM_001042492.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.(Val2259Ala)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001042492.2:c.6776T>C (p.Val2259Ala) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).

Multiple in silico predictors suggest a neutral effect: REVEL score 0.29, BayesDel score -0.045, and SpliceAI max delta 0.08 (BP4_Supporting).

ClinVar classifies this variant as Uncertain Significance (VariationID 826571, 1 clinical laboratory, criteria provided, single submitter).

No variant-specific functional studies, de novo observations, segregation data, or case-control evidence were identified for this variant.

With PM2 (supporting pathogenic) and BP4 (supporting benign) as the only met criteria, the evidence is insufficient to classify beyond Uncertain Significance. This classification is consistent with the existing ClinVar entry.

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	PVS1 is not applicable: NM_001042492.2:c.6776T>C is a missense variant (p.Val2259Ala), which does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No pathogenic variant with the same amino acid change at the same position has been identified as a comparator for PS1 application.
PS2	Not assessed	No de novo data are available for NM_001042492.2:c.6776T>C.
PS3	Not assessed	No variant-specific functional studies demonstrating a damaging effect for NM_001042492.2:c.6776T>C (p.Val2259Ala) were identified. OncoKB classifies this variant as having Unknown Oncogenic Effect.	oncokb
PS4	Not assessed	No case-control or variant-specific prevalence data are available for NM_001042492.2:c.6776T>C. The single ClinVar submission (VUS, 1 laboratory) does not provide proband counts or phenotype details.	clinvar
PS5	N/A	PS5 is not defined in the generic ACMG/AMP 2015 framework (PMID:25741868) and the NF1 VCEP criteria set (version 1.0.0) contains no rule payload to support application of this criterion.	cspec final_classification_framework
PM1	Not met	NM_001042492.2:c.6776T>C (p.Val2259Ala) is not located in a statistically significant mutational hotspot per CancerHotspots.org, nor within the well-established NF1 GRD (GAP-related domain, residues ~1198–1530). Position 2259 lies near the C-terminal domain boundary without functional domain assignment supporting PM1.
PM2	Met	NM_001042492.2:c.6776T>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency = 0). The variant meets PM2 at supporting level: absent from large population databases (AF < 0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variant at the same amino acid residue (p.Val2259) was identified as a comparator for PM5 application. Automated candidate harvesting returned zero same-residue candidates.	pm5_candidates
PM6	Not assessed	No de novo data are available for NM_001042492.2:c.6776T>C.
PP1	Not assessed	No cosegregation data are available for NM_001042492.2:c.6776T>C.
PP2	Not assessed	No gene-level missense constraint metrics (e.g., missense Z-score, HCI prior) were available for NF1 NM_001042492.2 to support PP2 application for this variant.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect: REVEL score 0.29 (below 0.5 threshold), BayesDel score -0.045 (benign-leaning), and SpliceAI max delta score 0.08 (no predicted splice impact).	revel bayesdel spliceai
PP4	Not assessed	No phenotype or clinical data are available for the proband carrying NM_001042492.2:c.6776T>C.
PP5	Not met	NM_001042492.2:c.6776T>C is classified as Uncertain Significance in ClinVar (VariationID 826571, 1 clinical laboratory, review status: criteria provided, single submitter). No reputable source has reported this variant as pathogenic.	clinvar
BA1	Not met	NM_001042492.2:c.6776T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF=0). Does not meet the >1% allele frequency threshold for BA1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_001042492.2:c.6776T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF=0). Does not meet the >0.3% allele frequency threshold for BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of NM_001042492.2:c.6776T>C in healthy adult individuals for a fully penetrant dominant disorder.
BS3	Not assessed	No variant-specific functional studies demonstrating no damaging effect for NM_001042492.2:c.6776T>C (p.Val2259Ala) were identified.	oncokb
BS4	Not assessed	No non-segregation data are available for NM_001042492.2:c.6776T>C.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the predominant mechanism, when the variant is observed in trans with a pathogenic variant. Neither a truncating mechanism predominance determination nor trans observation data are available for this variant; additionally, missense variants are a recognized disease mechanism in NF1.
BP2	Not assessed	No data are available regarding observation of NM_001042492.2:c.6776T>C in trans with a pathogenic NF1 variant.
BP4	Met	Multiple lines of computational evidence suggest no deleterious effect: REVEL score 0.29 (below 0.5 threshold, predicting neutral), BayesDel score -0.045 (benign-leaning), and SpliceAI max delta score 0.08 (no predicted splice impact).	revel bayesdel spliceai
BP5	Not assessed	No data are available regarding identification of NM_001042492.2:c.6776T>C in a case with an alternate molecular basis for disease.
BP6	Not met	NM_001042492.2:c.6776T>C is classified as Uncertain Significance in ClinVar (VariationID 826571). No reputable source has reported this variant as benign or likely benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_001042492.2:c.6776T>C is a missense variant (p.Val2259Ala), not a synonymous variant.

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