NM_002529.3:c.375C>A

NTRK1 · NP_002520.2:p.(Asn125Lys) · NM_002529.3

GRCh37: chr1:156836717 C>A · GRCh38: chr1:156866925 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.(Asn125Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002529.3:c.375C>A (p.Asn125Lys) is a missense variant in NTRK1 exon 4.

This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2).

This variant is absent from ClinVar and has not been reported in the published literature.

In silico predictions are contradictory: REVEL (0.683) supports a deleterious effect while BayesDel (0.055) supports a benign effect. SpliceAI predicts no significant splice impact (max delta 0.19). Neither PP3 nor BP4 can be met.

No functional, segregation, de novo, or case-control data are available for this variant. No variant-specific publications were identified.

PVS1 is not applicable as this is a missense variant, not a null variant.

Based on generic ACMG/AMP 2015 criteria, only PM2 (moderate) is met. With a single moderate criterion and no supporting evidence, 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.Asn125Lys) that does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No established pathogenic variant with the same amino acid change (p.Asn125Lys) has been reported in ClinVar or the literature.	clinvar
PS2	Not met	No de novo observation with confirmed paternity and maternity has been reported for this variant.
PS3	Not met	No functional data exists for this variant or for a systematically characterized range that includes position Asn125. OncoKB reports Unknown Oncogenic Effect, and no publications with variant-specific functional evidence were identified.	oncokb
PS4	Not met	The variant has not been observed in affected individuals; it is absent from ClinVar, COSMIC, and the published literature.	clinvar
PS5	Not met	No pathogenic missense variant has been identified at the same codon (Asn125) in ClinVar or the literature to support PS5.	clinvar pm5_candidates
PM1	Not met	This variant does not lie within a statistically significant mutational hotspot per cancerhotspots.org, and no CSPEC/VCEP-defined critical functional domain has been established for this region of NTRK1. While position 125 falls within an extracellular leucine-rich repeat domain, domain-level assignment of PM1 requires CSPEC/VCEP or literature-based domain definition, which is not available.
PM2	Met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% allele frequency in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No comparator missense variants at the same codon (Asn125) classified as pathogenic were identified in ClinVar; PM5 candidate harvesting returned zero candidates.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant in ClinVar or the published literature.
PP1	Not met	No cosegregation data are available; the variant has not been reported in families with NTRK1-related disease.
PP2	Not met	No gene-specific constraint metrics (HCI Prior, gnomAD missense Z-score) are available for NTRK1 to support the assertion that the gene has a low rate of benign missense variation.
PP3	Not met	In silico predictions are contradictory: REVEL score 0.683 supports a deleterious effect, but BayesDel score 0.055 strongly supports a benign effect. SpliceAI max delta 0.19 predicts no significant splice impact. Multiple lines of computational evidence do not converge on a deleterious prediction.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data are available to assess whether the clinical presentation is highly specific for NTRK1-related disease.
PP5	Not met	The variant is absent from ClinVar; no reputable source has reported it as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada; allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD; allele frequency does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available regarding observation of this variant in healthy adults, whether in trans with a pathogenic variant or at high frequency.
BS3	Not met	No well-established functional studies demonstrate a benign effect for this variant.
BS4	Not met	No family data are available to assess lack of segregation with disease.
BP1	Not met	NTRK1-related CIPA is caused by both missense and truncating mutations; missense variants are an established disease mechanism and BP1 does not apply.
BP2	Not met	CIPA is an autosomal recessive disorder; observation in trans with a pathogenic variant would be expected for affected individuals. No data are available to assess this criterion.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant; no phase data available for this variant.
PM4	N/A	PM4 applies to non-repeat indels causing protein-length change; this is a missense substitution.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
BP4	Not met	In silico predictions are contradictory and do not provide multiple lines of evidence supporting a benign effect: REVEL 0.683 supports a deleterious effect, while BayesDel 0.055 supports a benign effect. SpliceAI is neutral. Convergence on a benign prediction is not achieved.	revel bayesdel spliceai
BP5	Not met	No data are available showing this variant occurs in a case with an alternative molecular basis for disease.
BP6	Not met	The variant is absent from ClinVar; no reputable source has reported it as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants and intronic variants outside splice sites with no predicted splice impact. This is a missense substitution (p.Asn125Lys).

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.