NM_002529.3:c.334C>T

NTRK1 · NP_002520.2:p.(His112Tyr) · NM_002529.3

GRCh37: chr1:156834566 C>T · GRCh38: chr1:156864774 C>T

Gene: NTRK1 Transcript: NM_002529.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

NTRK1

Transcript

NM_002529.3

Protein

NP_002520.2:p.(His112Tyr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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).

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.His112Tyr) and does not fall into the ClinGen SVI PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant with the same amino acid change (H112Y) has been identified at this position in ClinVar or the literature.	clinvar
PS2	Not met	No de novo evidence is available for this variant. No literature reports describe this variant occurring de novo with confirmed maternity and paternity.
PS3	Not met	No functional studies have been identified for this variant or for a systematically characterized range that includes residue H112. OncoKB reports unknown oncogenic effect. COSMIC somatic observation (n=2) does not constitute experimental functional evidence.	oncokb
PS4	Not met	The variant is absent from ClinVar and no patient observations are reported in the literature. No clinical cohort data are available to assess enrichment in affected individuals.	clinvar
PS5	Not met	This variant is absent from ClinVar; no reputable source has classified it as pathogenic.	clinvar
PM1	Not met	Residue H112 is not located in a statistically significant mutational hotspot per cancerhotspots.org. No literature evidence specifically characterizes this residue as lying within a critical functional domain where missense variants are established to be pathogenic.
PM2	Met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare variant not observed in large population cohorts.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant has been identified at the same amino acid residue (H112) with a different amino acid change in ClinVar.	pm5_candidates
PM6	Not met	No de novo evidence is available for this variant. No literature reports describe a de novo occurrence with confirmed parentage.
PP1	Not met	No segregation data are available for this variant. No family studies have been reported.
PP2	Not met	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. Without evidence that the gene has a low rate of benign missense variation, PP2 cannot be applied.	pvs1_gene_context
PP3	Not met	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). No computational evidence supports a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data are available to assess whether the proband's phenotype is specific for NTRK1-related disease.
PP5	Not met	This variant is absent from ClinVar; no reputable source has classified it.	clinvar
BA1	N/A	The variant is absent from all population databases (allele frequency 0.0%) and does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	N/A	The variant is absent from all population databases (allele frequency 0.0%) and does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No homozygous or hemizygous observations of this variant have been reported in control populations without a disease phenotype. The variant is absent from all gnomAD cohorts.	gnomad_v2 gnomad_v4
BS3	Not met	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	Not met	No segregation or family studies are available to assess lack of co-segregation with disease.
BP1	Not met	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.	pvs1_gene_context
BP2	N/A	No data are available regarding co-occurrence of this variant in trans with a pathogenic NTRK1 variant.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No alternate molecular basis of disease has been identified. This variant has not been observed in a case where an alternative cause was found.
BP6	Not met	No reputable source classifies this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	This is a missense variant (c.334C>T, p.His112Tyr), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact and nucleotide-level conservation evidence.

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.