Variant classification summary

NM_002529.3:c.1334G>A

NTRK1 · NP_002520.2:p.(Arg445Lys) · NM_002529.3

GRCh37: chr1:156844780 G>A · GRCh38: chr1:156874988 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.(Arg445Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002529.3:c.1334G>A (p.Arg445Lys) is a missense variant in exon 11 of NTRK1.

2

This variant is absent from all population databases: gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0; PM2 met at moderate strength).

3

Multiple lines of computational evidence predict a benign effect: REVEL 0.277, BayesDel -0.176, SpliceAI max delta 0.00 (BP4 met at supporting benign strength).

4

No published literature, ClinVar submissions, or functional studies specific to this variant were identified.

5

NTRK1 loss-of-function variants cause autosomal recessive congenital insensitivity to pain with anhidrosis (CIPA); missense variants are a known disease mechanism.

6

Applying generic ACMG/AMP 2015 final classification rules (PMID:25741868): one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) are insufficient to classify as 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.1334G>A is a missense variant (p.Arg445Lys) in exon 11. It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Per ClinGen SVI PVS1 recommendations (PMC6185798), generic PVS1 framework is not applicable to this variant class.	pvs1_generic_framework
PS1	N/A	No alternative nucleotide change at c.1334 resulting in the same p.Arg445Lys amino acid change has been identified in ClinVar or the literature.
PS2	N/A	No de novo observation with confirmed paternity and maternity has been reported for this variant in any available source.
PS3	Not assessed	OncoKB reports Unknown Oncogenic Effect for NTRK1 R445K with no variant-specific reviewed functional evidence. No published functional studies of this variant were identified in the literature or curated databases.	oncokb
PS4	Not assessed	This variant is absent from ClinVar and no case-control or cohort studies reporting this variant in affected individuals were identified.
PS5	N/A	PS5 is not a standard criterion in the ACMG/AMP 2015 framework (Richards et al., PMID:25741868). No equivalent criterion exists in the generic ACMG/AMP classification rules being applied to this case.	generic_acmg_combination_rules
PM1	Not assessed	The variant maps to codon 445 within the tyrosine kinase domain of NTRK1, and is absent from population databases (gnomAD). However, no statistically significant mutational hotspot encompasses this residue, and explicit domain-level PM1 criteria (e.g., ClinGen domain constraint data) are not available for NTRK1 in the evidence packet.	gnomad_v2 gnomad_v4
PM2	Met	NM_002529.3:c.1334G>A is absent from all population databases: gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles). The variant has a population allele frequency of 0.0, well below the PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variants at the same residue (Arg445) with a different amino acid change were identified in ClinVar. PM5 candidate harvesting returned zero same-residue comparator variants.	pm5_candidates
PM6	N/A	No de novo observation (without confirmation of paternity and maternity) has been reported for this variant.
PP1	N/A	No co-segregation data are available for this variant. No family studies were identified in the literature or ClinVar.
PP2	Not assessed	NTRK1 is a disease gene for congenital insensitivity to pain with anhidrosis (CIPA), with missense variants reported as a known disease mechanism. However, HCI prior missense constraint data is not available for NTRK1, preventing formal quantification of the rate of benign missense variation required for PP2 application.
PP3	Not met	In silico tools uniformly predict a benign effect: REVEL score 0.277 (below the 0.5 threshold for pathogenicity), BayesDel score -0.176 (below the 0.27 threshold), and SpliceAI max delta score 0.00 (no predicted splice impact). Multiple lines of computational evidence do not support a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available for this case. The variant is absent from ClinVar and no clinical case reports were identified.
PP5	N/A	No reputable source (e.g., clinical diagnostic laboratory) has reported NM_002529.3:c.1334G>A as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0.0 does not meet the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0.0 does not meet the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No observations of this variant in healthy adults have been reported. Clinical phenotype data for any carriers are unavailable.
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of NM_002529.3:c.1334G>A (p.Arg445Lys) were identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.	oncokb
BS4	N/A	No segregation data are available for this variant. No family studies involving this variant were identified.
BP1	Not met	BP1 applies to missense variants in genes where only truncating variants cause disease. NTRK1-related CIPA is caused by both missense and truncating mutations, as documented in the literature. Therefore, missense variants are an established disease mechanism in NTRK1, and BP1 cannot be applied.
BP2	N/A	No observation of this variant in trans with a known pathogenic NTRK1 variant has been reported.
BP4	Met	Multiple lines of computational evidence predict no deleterious impact: REVEL score 0.277 (pathogenic threshold ≥0.5 not met), BayesDel score -0.176 (pathogenic threshold ≥0.27 not met), and SpliceAI max delta score 0.00 (no splicing impact predicted). All three in silico tools uniformly predict a benign effect.	revel bayesdel spliceai
BP5	N/A	No observation of this variant in a case with an established alternate molecular basis for disease has been reported.
BP6	N/A	No reputable source has classified NM_002529.3:c.1334G>A as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	NM_002529.3:c.1334G>A is a missense variant (p.Arg445Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	Skipped per user instruction: variant is a substitution, BP3 applies to in-frame indels in repeat regions.
PM3	N/A	Skipped per user instruction: no evidence relevant to this criterion available.
PM4	N/A	Skipped per user instruction: variant is a substitution, PM4 applies to in-frame deletions/insertions and stop-loss variants.

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.