NM_002529.3:c.737C>T

NTRK1 · NP_002520.2:p.(Ser246Phe) · NM_002529.3

GRCh37: chr1:156841434 C>T · GRCh38: chr1:156871642 C>T

Gene: NTRK1 Transcript: NM_002529.3

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

NTRK1

Transcript

NM_002529.3

Protein

NP_002520.2:p.(Ser246Phe)

gnomAD AF

6.195748477394811e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002529.3:c.737C>T (p.Ser246Phe) is a missense variant in NTRK1, a gene associated with autosomal recessive congenital insensitivity to pain with anhidrosis (CIPA).

This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (1/1,614,010 alleles; overall AF=6.20×10⁻⁷; highest subpopulation AF=1.10×10⁻⁵ in South Asian), satisfying PM2 at moderate strength.

Multiple in silico tools predict a benign effect: REVEL score of 0.132, BayesDel score of -0.415, and SpliceAI max delta of 0.01. These support BP4 at supporting benign strength.

This missense variant is not eligible for PVS1 as it does not fall into the null-variant buckets of nonsense, frameshift, or canonical splice site variants per ClinGen SVI PVS1 recommendations (PMC6185798).

No functional studies, de novo reports, segregation data, case-control data, or ClinVar classifications exist for this variant. No publications mention NM_002529.3:c.737C>T.

The evidence profile consists of PM2 (moderate) and BP4 (supporting benign). Under generic ACMG/AMP 2015 combination rules, this combination does not meet the threshold for pathogenic, likely pathogenic, benign, or likely benign classification, and the variant therefore remains 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	NM_002529.3:c.737C>T is a missense variant (p.Ser246Phe) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_generic_framework
PS1	Not met	No alternate nucleotide change at codon 737 resulting in the same p.(Ser246Phe) amino acid change has been established as pathogenic. The variant is absent from ClinVar, and no literature reports an alternate nucleotide substitution producing the same protein change.	clinvar
PS2	Not met	No de novo observation has been reported for NM_002529.3:c.737C>T. No publications were identified that describe a de novo occurrence of this variant.
PS3	Not met	No functional studies have been identified for p.(Ser246Phe) or for a systematically characterized range that includes residue 246. OncoKB classifies this variant as 'Unknown Oncogenic Effect.' The COSMIC somatic count (n=1) does not constitute functional evidence. No publications reported experimental characterization of this variant.	oncokb
PS4	Not met	This variant is absent from ClinVar and no affected individuals have been reported in the literature with NM_002529.3:c.737C>T. The single COSMIC entry is somatic and does not contribute to germline PS4. No case-control or cohort data are available.	clinvar
PS5	Not met	No segregation or family history data are available for NM_002529.3:c.737C>T. No publications report this variant in a familial context.
PM1	Not met	Residue 246 in NTRK1 is not located in a statistically significant mutational hotspot per cancerhotspots.org. While NTRK1 has a well-characterized functional architecture (extracellular LRR domains, transmembrane domain, tyrosine kinase domain), no domain-level characterization specific to the region containing p.Ser246 was identified in the case evidence that would unambiguously establish it as a critical functional domain with an absence of benign variation.
PM2	Met	NM_002529.3:c.737C>T is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (1/1,614,010 alleles, overall AF=6.20×10⁻⁷; highest subpopulation AF=1.10×10⁻⁵ in South Asian, 1/91,076 alleles). The total population allele frequency is well below the 0.1% threshold for PM2 in a non-VCEP framework.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue ClinVar comparator variants were identified at codon 246 of NTRK1. PM5 candidate harvesting returned zero candidates, and the automatic PM5 pipeline could not establish classic same-residue comparator semantics.
PM6	Not met	No de novo observation has been reported for NM_002529.3:c.737C>T in any publication or database. De novo occurrence without confirmation of paternity/maternity could not be assessed.
PP1	Not met	No co-segregation data are available for NM_002529.3:c.737C>T. No family studies reporting this variant were identified.
PP2	Not assessed	NTRK1 is associated with CIPA (congenital insensitivity to pain with anhidrosis), an autosomal recessive disorder, and loss-of-function missense variants are a recognized disease mechanism. However, no gene-level missense constraint metrics (e.g., Z-score, gnomAD missense constraint) were available in the case materials to evaluate whether NTRK1 has a low rate of benign missense variation. PP2 cannot be reliably assessed without these metrics.
PP3	Not met	Multiple in silico tools do not support a deleterious effect for p.(Ser246Phe). REVEL score is 0.132 (below the 0.5 pathogenic threshold), and BayesDel score is -0.415 (consistent with a benign prediction). SpliceAI max delta score is 0.01, indicating no predicted splicing impact. No HCI prior probability is available for NTRK1. No computational evidence supports pathogenicity.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data are available for NM_002529.3:c.737C>T. The variant is absent from ClinVar and no case reports describe the phenotype of individuals harboring this variant.
PP5	Not met	NM_002529.3:c.737C>T is absent from ClinVar and has not been reported as pathogenic by any reputable source. No ClinVar submissions, expert panel reviews, or published classifications are available for this variant.	clinvar
BA1	Not met	The allele frequency of NM_002529.3:c.737C>T in gnomAD v4.1 is 6.20×10⁻⁷ (0.000062%), far below the 1% non-VCEP BA1 threshold. The highest subpopulation frequency is 1.10×10⁻⁵ (0.0011%) in the South Asian population, also well below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency of NM_002529.3:c.737C>T is 6.20×10⁻⁷ (0.000062%), far below the 0.3% non-VCEP BS1 threshold. The highest subpopulation frequency is 1.10×10⁻⁵ (0.0011%), also well below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals have been observed in gnomAD v2.1 or v4.1 for NM_002529.3:c.737C>T. No observations in trans with a known pathogenic NTRK1 variant have been reported. BS2 criteria are not satisfied.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate a neutral or non-damaging effect for p.(Ser246Phe). No publications report experimental characterization of this variant. OncoKB reports 'Unknown Oncogenic Effect.'	oncokb
BS4	Not met	No segregation data are available for NM_002529.3:c.737C>T. Lack of segregation in affected family members cannot be evaluated.
BP1	Not met	NTRK1 is associated with CIPA, and both missense and truncating variants are established disease mechanisms. Over 105 mutations have been reported, including many missense variants. BP1 is applicable only when a gene's disease is caused primarily by truncating variants, which is not the case for NTRK1.
BP2	Not met	BP2 applies to observation in trans with a pathogenic variant in a fully penetrant dominant disorder. CIPA is an autosomal recessive disorder, and no trans observations are available for this variant. BP2 criteria are not satisfied.
BP4	Met	Multiple lines of computational evidence suggest p.(Ser246Phe) does not have a deleterious effect. REVEL score is 0.132 (below the 0.5 pathogenic threshold), BayesDel score is -0.415 (consistent with a benign prediction), and SpliceAI max delta score is 0.01 (no predicted splicing impact). All available in silico tools are concordant in predicting a non-damaging effect.	revel bayesdel spliceai
BP5	Not met	No case has been reported in which NM_002529.3:c.737C>T was found in an individual with an alternate molecular basis for disease. BP5 cannot be evaluated without such data.
BP6	Not met	NM_002529.3:c.737C>T is absent from ClinVar and has not been reported as benign by any reputable source. No ClinVar submissions or published classifications describe this variant as benign.	clinvar
BP7	N/A	NM_002529.3:c.737C>T is a missense variant (p.Ser246Phe), not a synonymous/silent variant. BP7 is only applicable to synonymous variants that do not affect splicing.

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