NM_002529.3:c.316G>A

NTRK1 · NP_002520.2:p.(Val106Met) · NM_002529.3

GRCh37: chr1:156834548 G>A · GRCh38: chr1:156864756 G>A

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.(Val106Met)

gnomAD AF

9.913430964105944e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002529.3:c.316G>A (p.Val106Met) in NTRK1 was identified as a rare missense variant in exon 3 of the extracellular domain.

This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.00080% (2/251,148 alleles) and gnomAD v4.1 AF=0.00099% (16/1,613,972 alleles), with no homozygotes observed, meeting PM2 at moderate strength for an autosomal recessive disorder.

Multiple lines of computational evidence predict no deleterious effect: REVEL score is 0.175 (below the pathogenic threshold of 0.5), BayesDel is -0.235671 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta 0.05), meeting BP4 at supporting benign level.

This variant has been reported in ClinVar as Uncertain significance (ClinVar ID 655441) by three clinical laboratories (2-star review status). No expert panel has reviewed this variant, and no submitter has asserted a pathogenic or benign classification.

No variant-specific functional studies, segregation data, de novo reports, case-control data, or family studies were identified for NM_002529.3:c.316G>A. OncoKB reports 'Unknown Oncogenic Effect' with no reviewed variant-specific evidence. COSMIC reports one somatic occurrence (COSV100693989) without functional assay data.

Applying the generic ACMG/AMP 2015 final classification combination rules (PMID:25741868), the met criteria are PM2 (moderate pathogenic) and BP4 (supporting benign). These criteria are contradictory and do not satisfy any pathogenic or likely pathogenic combination, nor any benign or likely benign combination. The variant is classified as 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	PVS1 is not applicable to missense variants. NM_002529.3:c.316G>A is a missense substitution (NP_002520.2:p.Val106Met) and does not fall into any PVS1 null-variant category (nonsense, frameshift, canonical splice ±1/2, initiation codon, or exon deletion).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence that a different nucleotide change at codon 106 resulting in the same missense change (p.Val106Met) has been previously established as pathogenic.	clinvar pm5_candidates
PS2	Not met	No de novo data available for this variant. No publications or case submissions report a confirmed de novo occurrence of NM_002529.3:c.316G>A with confirmed parentage.	clinvar
PS3	Not met	No variant-specific functional studies have been performed on p.Val106Met. OncoKB reports 'Unknown Oncogenic Effect' with no reviewed functional evidence. No publications directly tested this variant or a systematically characterized range spanning codon 106 in a functional assay.	oncokb
PS4	Not met	No case-control or cohort data demonstrate enrichment of this variant in affected individuals compared to controls. ClinVar shows 3 clinical laboratories classify this variant as VUS with no variant-specific case counts or prevalence data.	clinvar gnomad_v2 gnomad_v4
PS5	Not met	No reputable source has classified this variant as pathogenic. ClinVar classification is Uncertain significance (2-star review status), and no expert panel or clinical laboratory has asserted a pathogenic or likely pathogenic classification.	clinvar
PM1	Not met	Residue Val106 does not lie in a statistically significant mutational hotspot per cancerhotspots.org, and no domain-specific functional evidence in the case materials establishes that the extracellular region spanning codon 106 is a critical functional domain where missense variants are established as pathogenic.
PM2	Met	This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.00080% (2/251,148 alleles), gnomAD v4.1 AF=0.00099% (16/1,613,972 alleles), both well below the 0.1% threshold for PM2. NTRK1-associated congenital insensitivity to pain with anhidrosis (CIPA) follows autosomal recessive inheritance, making PM2 applicable for variants at extremely low frequency in controls. No homozygotes have been observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No different missense variant at the same residue (Val106) has been established as pathogenic. The PM5 candidates search found no comparator variants at codon 106 in ClinVar.	pm5_candidates
PM6	Not met	No de novo data with or without confirmed paternity available for this variant.	clinvar
PP1	Not met	No segregation data available for this variant. No family studies or cosegregation analyses have been reported.
PP2	Not assessed	Insufficient data to evaluate. gnomAD constraint metrics (missense z-score, o/e ratio) for NTRK1 were not provided in the case materials, and no gene-level missense constraint analysis was included in the evidence brief. Cannot determine whether NTRK1 has a low rate of benign missense variation.
PP3	Not met	Multiple in silico predictors suggest a benign effect rather than a deleterious one. REVEL score is 0.175 (below the typical pathogenic threshold of 0.5), BayesDel score is -0.235671 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta 0.05). These scores are concordant with BP4, not PP3.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data specific to this variant were available in the case materials. The variant has been observed in clinical testing (ClinVar submissions for hereditary insensitivity to pain with anhidrosis and inborn genetic diseases), but no detailed phenotype descriptions were provided.	clinvar
PP5	Not met	No reputable source has classified this variant as pathogenic. ClinVar consensus is Uncertain significance (2-star, criteria provided, multiple submitters, no conflicts). The GeneReviews article PMID:20301726 is a general NTRK1 CIPA overview; without full text, variant-specific mention cannot be confirmed.	clinvar
BA1	Not met	Allele frequency is far below the BA1 threshold of 1%. The highest population frequency in gnomAD is 0.0044% (South Asian, v4.1) and the overall AF is 0.00099% (v4.1).	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency is below the BS1 threshold of 0.3%. The overall gnomAD v4.1 AF is 0.00099% and the highest subpopulation AF is 0.0044% (South Asian).	gnomad_v2 gnomad_v4
BS2	Not met	No evidence that this variant has been observed in a healthy adult individual in trans with a known pathogenic variant in NTRK1. NTRK1-associated CIPA is autosomal recessive, so BS2 requires observation in trans with a pathogenic variant in an unaffected individual.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate that this variant has no deleterious effect. While in silico predictors (REVEL 0.175, BayesDel -0.235671) are concordant with a benign interpretation, these are computational, not experimental, and are addressed under BP4.	revel bayesdel oncokb
BS4	Not met	No segregation data available to evaluate lack of cosegregation with disease.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. NTRK1-associated CIPA is caused by both missense and truncating/loss-of-function variants. Multiple missense mutations across the NTRK1 gene are documented as pathogenic in CIPA patients. BP1 does not apply.	pvs1_gene_context
BP2	Not met	No evidence of this variant observed in trans with a known pathogenic variant in NTRK1.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.175 (below the 0.5 threshold, favoring benign), BayesDel score is -0.235671 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta score 0.05). All available in silico tools are concordant toward a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No evidence that this variant has been observed in a case with an alternate molecular basis for disease. No co-occurring pathogenic variant data available.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar classification is Uncertain significance (2-star, 3 submitters), not Benign or Likely benign.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants. NM_002529.3:c.316G>A is a missense variant (p.Val106Met), not a synonymous or intronic variant.

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