Variant classification summary

NM_002529.3:c.1065C>A

NTRK1 · NP_002520.2:p.(Asn355Lys) · NM_002529.3

GRCh37: chr1:156843639 C>A · GRCh38: chr1:156873847 C>A

Gene: NTRK1 Transcript: NM_002529.3

Final call

VUS

PM2 moderate

Variant details

Gene

NTRK1

Transcript

NM_002529.3

Protein

NP_002520.2:p.(Asn355Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002529.3:c.1065C>A (p.Asn355Lys) is a missense variant in NTRK1, a gene in which loss-of-function variants cause autosomal recessive congenital insensitivity to pain with anhidrosis (CIPA).

2

This variant is absent from large population databases (gnomAD v2.1 and v4.1), supporting PM2 at moderate strength.

3

In silico predictors are inconclusive: REVEL score is 0.372 (intermediate, not reaching pathogenic thresholds) and BayesDel is -0.315 (benign-leaning). SpliceAI predicts no splicing impact (max delta = 0.00). PP3 and BP4 are not met.

4

No functional studies, de novo reports, cosegregation data, or ClinVar submissions were identified for this variant. PVS1 does not apply as the variant is a missense substitution, not a null variant.

5

Only PM2 (moderate) is met. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), a single moderate criterion is insufficient to reach Likely Pathogenic or Likely Benign. The 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	NM_002529.3:c.1065C>A is a missense variant (p.Asn355Lys), not a predicted null variant (nonsense, frameshift, or canonical splice ±1/2). Under the generic PVS1 framework (PMC6185798), missense variants do not qualify for PVS1.	pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context
PS1	Not assessed	No evidence of a different nucleotide change at codon 355 producing the same p.Asn355Lys missense that has been previously classified as pathogenic.
PS2	Not assessed	No reports of a confirmed de novo occurrence (with maternity and paternity confirmed) of NM_002529.3:c.1065C>A were identified in the available evidence.
PS3	Not assessed	No well-established functional studies specifically evaluating the p.Asn355Lys variant were identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence reviewed.	oncokb
PS4	Not assessed	The variant is absent from ClinVar in the primary evidence pipeline, so no affected proband counts or case-control comparison data are available. Prevalence of the variant in affected individuals versus controls cannot be assessed.	clinvar
PS5	N/A	No established pathogenic variant at the same amino acid position (p.Asn355) was identified through the PM5 candidate search. PS5 requires a strong body of evidence linking the same residue to pathogenicity, which is not available.	pm5_candidates
PM1	Not assessed	Residue Asn355 is located in the leucine-rich repeat C-terminal (LRRCT) domain of NTRK1, a functionally important extracellular region. However, formal constraint data (e.g., gnomAD missense Z-score or domain-level observed/expected ratios) confirming a mutational hotspot with absence of benign variation in this domain was not retrieved.
PM2	Met	NM_002529.3:c.1065C>A is absent from both gnomAD v2.1 and gnomAD v4.1, large population databases encompassing over 250,000 alleles combined. This supports moderate evidence under PM2 (absent from population controls).	gnomad_v2 gnomad_v4
PM5	N/A	No pathogenic missense variant at the same amino acid residue (p.Asn355) with a different amino acid change was identified. The PM5 candidate search returned zero same-residue comparator candidates.	pm5_candidates
PM6	Not assessed	No report of a presumed de novo occurrence (without confirmation of maternity/paternity) was identified for NM_002529.3:c.1065C>A in the available evidence.
PP1	Not assessed	No cosegregation data for NM_002529.3:c.1065C>A with CIPA or other NTRK1-related disease in multiple affected family members was identified in the available evidence.
PP2	Not assessed	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. HCI prior data is not available for NTRK1, and formal gene-level missense constraint metrics were not retrieved in the case evidence.
PP3	Not met	Multiple in silico tools do not consistently predict a deleterious effect. REVEL score is 0.372 (intermediate, below standard pathogenic thresholds of 0.5–0.7). BayesDel score is -0.315 (benign-leaning). SpliceAI max delta is 0.00 (no predicted splicing impact). These results do not support PP3.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype information is available for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not assessed	The variant is absent from ClinVar, and no reputable source (e.g., clinical diagnostic laboratory, expert panel) has reported this variant as pathogenic.	clinvar
BA1	Not met	NM_002529.3:c.1065C>A is absent from gnomAD v2.1 and v4.1. The allele frequency is effectively 0%, far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	NM_002529.3:c.1065C>A is absent from gnomAD v2.1 and v4.1. The allele frequency is effectively 0%, far below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on observation of NM_002529.3:c.1065C>A in healthy adult individuals with full penetrance expected at an early age. BS2 cannot be applied without such observations.
BS3	Not assessed	No well-established functional studies demonstrating that p.Asn355Lys has no damaging effect on protein function were identified.
BS4	Not assessed	No families were identified in which NM_002529.3:c.1065C>A fails to segregate with disease (i.e., non-segregation data).
BP1	N/A	Congenital insensitivity to pain with anhidrosis (CIPA) is caused by both truncating and missense NTRK1 mutations. Over 105 NTRK1 mutations have been reported in CIPA, and missense variants are a well-established disease mechanism. BP1 (missense variant in a gene where primarily truncating variants cause disease) does not apply.
BP2	Not assessed	No data on observation of NM_002529.3:c.1065C>A in trans with a known pathogenic NTRK1 variant in an unaffected individual, or in cis with a pathogenic variant in a fully penetrant dominant disorder.
BP4	Not met	Multiple in silico tools do not consistently predict no impact. BayesDel is -0.315 (benign-leaning) but REVEL is 0.372 (intermediate, not in the benign range). SpliceAI delta is 0.00 (no splicing impact), but the missense in silico predictors collectively do not provide multiple lines of evidence for a benign effect.	revel bayesdel spliceai
BP5	Not assessed	No case was identified where NM_002529.3:c.1065C>A was found in an individual with an alternate molecular basis for disease that would suggest the variant is not causative.
BP6	Not assessed	The variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign.	clinvar
BP7	N/A	NM_002529.3:c.1065C>A is a missense variant (p.Asn355Lys), not a synonymous (silent) variant. BP7 applies only to synonymous variants with no predicted splicing impact.
BP3	N/A	Variant is a single-nucleotide substitution, not an in-frame deletion or insertion in a repetitive region. BP3 does not apply.
PM3	N/A	Explicitly skipped per adjudication instructions; not in the only-assess list.
PM4	N/A	Variant is a single-nucleotide substitution, not an in-frame deletion/insertion or stop-loss variant. PM4 does not apply.

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