NM_001042492.3:c.3496G>C

NF1 · NP_001035957.1:p.(Gly1166Arg) · NM_001042492.3

GRCh37: chr17:29559899 G>C · GRCh38: chr17:31232881 G>C

Gene: NF1 Transcript: NM_001042492.3

Final call

VUS

PM2 moderate PP3 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.3

Protein

NP_001035957.1:p.(Gly1166Arg)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001042492.3:c.3496G>C (p.Gly1166Arg) is a missense variant in NF1 affecting the last nucleotide of exon 26.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at moderate strength.

SpliceAI predicts a donor loss at the exon 26–intron 26 boundary with a delta score of 0.76, meeting PP3 at supporting strength.

This variant has been reported in ClinVar as Pathogenic by Ambry Genetics and Likely pathogenic by GeneDx, both with criteria provided, single submitter review status.

No variant-specific functional data (PS3), de novo reports (PS2/PM6), or co-segregation data (PP1/BS4) are available.

Two publications associated with this variant via ClinVar (PMID:24789688, PMID:25394175) were reviewed; neither mentions NM_001042492.3:c.3496G>C specifically.

The NF1 ClinGen Neurofibromatosis and Schwannomatosis Expert Panel specification (Version 1.0) contains no structured criteria rules; assessment follows generic ACMG/AMP 2015 framework.

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	NM_001042492.3:c.3496G>C is a missense variant (p.Gly1166Arg); it does not fall into the default PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	PS1 requires the same amino acid change via a different nucleotide substitution; no evidence of an alternative nucleotide change producing p.Gly1166Arg was identified.
PS2	Not met	No de novo occurrence data (maternity/paternity confirmed) was identified for this variant in any available source.
PS3	Not met	No experimental functional data exists for NM_001042492.3:c.3496G>C or a systematically characterized range that includes it. OncoKB reports no variant-specific reviewed functional evidence. SpliceAI predicts a donor loss (delta 0.76) but this is in silico prediction, not functional data.	oncokb spliceai
PS4	Not met	ClinVar submission SCV002617250 (Ambry Genetics) states the variant has been detected in multiple unrelated individuals with NF1 clinical suspicion, but no specific case counts, allele frequencies in cases vs controls, or statistical analysis are available. Without quantifiable data, PS4 cannot be met.	clinvar
PS5	Not met	No established pathogenic variant at the same position with a different amino acid change was identified. The ClinVar classification for this variant is 'criteria provided, single submitter' (not 3-star expert panel), which does not independently satisfy PS5 under the applied framework.	clinvar
PM1	Not met	Position Gly1166 is not located within a statistically significant mutational hotspot (cancerhotspots.org reports no significant hotspot at this residue). No VCEP/CSPEC-defined critical functional domain encompasses this residue. The variant lies outside the GRD (GAP-related domain, residues ~1198–1530) and no published evidence identifies this position as a critical functional domain.
PM2	Met	NM_001042492.3:c.3496G>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), indicating it is not a common population variant and meets PM2 at moderate strength (allele frequency <0.1% in all population databases queried).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant; NF1 is an autosomal dominant disorder.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions, stop-loss, or initiation codon variants; this is a missense substitution.
PM5	N/A	No same-residue comparator variants (different missense change at Gly1166 classified as pathogenic) were identified in ClinVar. PM5 candidate harvesting returned zero candidates.	pm5_candidates
PM6	Not met	No de novo occurrence data (maternity/paternity confirmed) was identified for this variant.
PP1	Not assessed	No co-segregation data is available for this variant.
PP2	Not assessed	No HCI prior score or gene-level missense constraint metric is available for NF1 to determine whether the gene has a low rate of benign missense variation. The NF1 VCEP specification does not provide PP2 guidance.
PP3	Met	SpliceAI predicts a significant donor loss at the exon 26–intron 26 boundary (DS_DL = 0.76, well above the 0.2 threshold), consistent with the variant altering the last nucleotide of exon 26 (c.3496G>C at position −1 of the donor splice site). REVEL (0.51) is borderline; BayesDel (0.053) is below the pathogenic threshold. The SpliceAI donor loss prediction provides in silico support for a deleterious effect.	spliceai revel bayesdel
PP4	Not assessed	No patient phenotype or clinical data is available for this case. PP4 requires that the patient's phenotype is highly specific to the gene/disease.
PP5	Not met	ClinVar classification is 'Pathogenic' and 'Likely pathogenic' with review status 'criteria provided, single submitter' (not 3-star expert panel). Under the applied framework, PP5 at supporting strength requires ClinVar 3-star expert panel review, which is not met. Neither cited ClinVar submission (Ambry Genetics, GeneDx) represents an expert panel classification.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. BA1 requires an allele frequency >1%, which is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases. BS1 requires an allele frequency >0.3%, which is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on observation in healthy adults (e.g., homozygous or in trans with a pathogenic variant) is available.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this variant.
BS4	Not assessed	No co-segregation data is available to evaluate lack of segregation with disease.
BP1	N/A	NF1 is associated with numerous pathogenic missense variants; disease is not caused exclusively by truncating variants.
BP2	Not assessed	No data on observation in trans with a pathogenic variant in a recessive disorder (NA — NF1 is autosomal dominant).
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
BP4	Not met	Multiple in silico tools predict a deleterious effect. SpliceAI predicts a donor loss with delta score 0.76. REVEL score (0.51) is borderline pathogenic. The evidence does not support a benign in silico consensus.	spliceai revel bayesdel
BP5	Not met	No ClinVar submission classifies this variant as benign or likely benign. The variant is reported as Pathogenic and Likely pathogenic by two clinical laboratories.	clinvar
BP6	Not met	ClinVar classification is Pathogenic/Likely pathogenic; BP6 requires a reputable source to classify the variant as benign. Additionally, no 3-star expert panel benign classification exists.	clinvar
BP7	N/A	BP7 applies to synonymous variants without splice impact; this is a missense variant (p.Gly1166Arg).

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.