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.1 SpliceAI predicts a donor loss at the exon 26–intron 26 boundary with a delta score of 0.76, meeting PP3 at supporting strength.2 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.3 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.4 The NF1 ClinGen Neurofibromatosis and Schwannomatosis Expert Panel specification (Version 1.0) contains no structured criteria rules; assessment follows generic ACMG/AMP 2015 framework.5
NF1
Final classification
VUS
NF1 c.3496G>C · p.Gly1166Arg
NF1
NM_001042492.3:c.3496G>C (p.Gly1166Arg) is a missense variant in NF1 affecting the last nucleotide of exon 26.
ClinGen Neurofibromatosis and Schwannomatosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NF1 Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, PP3 supporting; combination = 1 moderate + 1 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
NF1 c.3496G>C
PM2 + PP3
→
VUS
5
cspec ↗generic_acmg_combination_rules
Gene diagram
· NM_001042492.3 · variants mapped to exon structure
NF1
NM_001042492.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
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).
Absent from gnomAD v2.1.Absent from gnomAD v4.1.Absent from gnomAD-Canada v1.0.
✓
PP3
supporting
Pathogenic
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 delta score (donor loss) = 0.76predicting disruption of the exon 26 donor splice site.REVEL = 0.51 (borderline pathogenic).
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data (maternity/paternity confirmed) was identified for this variant in any available source.
PS3
No experimental functional data exists for NM_001042492.3:c.3496G>C or a systematically characterized range that includes it.
PS4
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.
PM1
Position Gly1166 is not located within a statistically significant mutational hotspot (cancerhotspots.org reports no significant hotspot at this residue).
PM6
No de novo occurrence data (maternity/paternity confirmed) was identified for this variant.
PP1
No co-segregation data is available for this variant.
PP2
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.
PP4
No patient phenotype or clinical data is available for this case.
PP5
ClinVar classification is 'Pathogenic' and 'Likely pathogenic' with review status 'criteria provided, single submitter' (not 3-star expert panel).
Benign
BA1
The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada.
BS1
The variant is absent from all population databases.
BS2
No data on observation in healthy adults (e.g., homozygous or in trans with a pathogenic variant) is available.
BS3
No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this variant.
BS4
No co-segregation data is available to evaluate lack of segregation with disease.
BP2
No data on observation in trans with a pathogenic variant in a recessive disorder (NA — NF1 is autosomal dominant).
BP4
Multiple in silico tools predict a deleterious effect.
BP5
No ClinVar submission classifies this variant as benign or likely benign.
BP6
ClinVar classification is Pathogenic/Likely pathogenic; BP6 requires a reputable source to classify the variant as benign.
N/A · 8
PVS1 · PS1 · PM3 · PM4 · PM5 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 1731988)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.76). REVEL score = 0.51. BayesDel score = 0.0531436.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NF1, a negative regulator of RAS, is inactivated by mutation or deletion in various solid and hematologic malignancies.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 2 PMIDs not cited in assessment
24789688 ↗
Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing.
CLINVAR
25394175 ↗
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.
CLINVAR