PM2 (supporting) is met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, indicating it is rare in the general population.1 BP4 (supporting benign) is met: multiple computational predictors (REVEL 0.091, BayesDel -0.484, SpliceAI max delta 0.05) uniformly predict no significant impact on protein function or splicing.2 PVS1 is not applicable as this is a missense variant not falling into null-variant categories. No functional studies (PS3/BS3), clinical observations (PS4), de novo data (PS2/PM6), segregation data (PP1/BS4), or ClinVar classifications (PS5/PP5/BP6) are available. With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is indeterminate. Using the generic ACMG/AMP 2015 combination rules (PMID:25741868), this variant is classified as a variant of uncertain significance (VUS).3
NTRK1
Final classification
VUS
NTRK1 c.334C>T · p.His112Tyr
NTRK1
PM2 (supporting) is met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, indicating it is rare in the general population.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
NTRK1 c.334C>T
PM2 + BP4
→
VUS
Gene diagram
· NM_002529.3 · variants mapped to exon structure
NTRK1
NM_002529.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare variant not observed in large population cohorts.
Absent from gnomAD v2.1 (exomes). Absent from gnomAD v4.1 (exomes). Absent from gnomAD-Canada v1.0 (genomes).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on gene product: REVEL score 0.091 (well below pathogenic threshold), BayesDel score -0.484 (benign range), and SpliceAI max delta score 0.05 (no predicted splicing alteration).
REVEL: 0.091. BayesDel: -0.484. SpliceAI max delta: 0.05.
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic variant with the same amino acid change (H112Y) has been identified at this position in ClinVar or the literature.
PS2
No de novo evidence is available for this variant.
PS3
No functional studies have been identified for this variant or for a systematically characterized range that includes residue H112.
PS4
The variant is absent from ClinVar and no patient observations are reported in the literature.
PM1
Residue H112 is not located in a statistically significant mutational hotspot per cancerhotspots.org.
PM5
No pathogenic missense variant has been identified at the same amino acid residue (H112) with a different amino acid change in ClinVar.
PM6
No de novo evidence is available for this variant.
PP1
No segregation data are available for this variant.
PP2
While NTRK1 loss-of-function is an established disease mechanism for congenital insensitivity to pain with anhidrosis (CIPA), HCI prior constraint data are not available for NTRK1.
PP3
Multiple in silico predictors uniformly support a benign interpretation: REVEL score 0.091 (well below 0.5 threshold), BayesDel score -0.484 (negative/benign range), and SpliceAI max delta 0.05 (no predicted splicing impact).
PP4
No patient phenotype or clinical data are available to assess whether the proband's phenotype is specific for NTRK1-related disease.
PP5
This variant is absent from ClinVar; no reputable source has classified it.
Benign
BS2
No homozygous or hemizygous observations of this variant have been reported in control populations without a disease phenotype.
BS3
No in vitro or in vivo functional studies have been identified that demonstrate no damaging effect on protein function or splicing for this variant.
BS4
No segregation or family studies are available to assess lack of co-segregation with disease.
BP1
NTRK1-associated congenital insensitivity to pain with anhidrosis (CIPA) is caused by both missense and truncating loss-of-function variants; missense is an established disease mechanism for this gene, so BP1 does not apply.
BP5
No alternate molecular basis of disease has been identified.
BP6
No reputable source classifies this variant as benign.
N/A · 5
PVS1 · BA1 · BS1 · BP2 · 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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.091. BayesDel score = -0.484273.
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. NTRK1, a receptor tyrosine kinase, is altered by gene fusions in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62325616, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links