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).1 This variant is absent from ClinVar and has not been reported in the published literature.2 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.3 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.4 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).5
NTRK1
Final classification
VUS
NTRK1 c.375C>A · p.Asn125Lys
NTRK1
NM_002529.3:c.375C>A (p.Asn125Lys) is a missense variant in NTRK1 exon 4.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate; combination = 1 moderate, which maps to VUS.
Classification rationale
PM2
VUS
NTRK1 c.375C>A
PM2
→
VUS
3
revelbayesdelspliceai ↗
4
pvs1_generic_framework ↗pvs1_variant_assessment
5
generic_acmg_combination_rules
Gene diagram
· NM_002529.3 · variants mapped to exon structure
NTRK1
NM_002529.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
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.
Absent from gnomAD v2.1 (0 alleles).Absent from gnomAD v4.1 (0 alleles).Absent from gnomAD-Canada v1.0 (0 alleles).
Assessed · not applied
Pathogenic
PS1
No established pathogenic variant with the same amino acid change (p.Asn125Lys) has been reported in ClinVar or the literature.
PS2
No de novo observation with confirmed paternity and maternity has been reported for this variant.
PS3
No functional data exists for this variant or for a systematically characterized range that includes position Asn125.
PS4
The variant has not been observed in affected individuals; it is absent from ClinVar, COSMIC, and the published literature.
PM1
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.
PM6
No de novo observation has been reported for this variant in ClinVar or the published literature.
PP1
No cosegregation data are available; the variant has not been reported in families with NTRK1-related disease.
PP2
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
In silico predictions are contradictory: REVEL score 0.683 supports a deleterious effect, but BayesDel score 0.055 strongly supports a benign effect.
PP4
No patient phenotype data are available to assess whether the clinical presentation is highly specific for NTRK1-related disease.
PP5
The variant is absent from ClinVar; no reputable source has reported it as pathogenic.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada; allele frequency does not exceed the 1% BA1 threshold.
BS1
The variant is absent from gnomAD; allele frequency does not exceed the 0.3% BS1 threshold.
BS2
No data are available regarding observation of this variant in healthy adults, whether in trans with a pathogenic variant or at high frequency.
BS3
No well-established functional studies demonstrate a benign effect for this variant.
BS4
No family data are available to assess lack of segregation with disease.
BP1
NTRK1-related CIPA is caused by both missense and truncating mutations; missense variants are an established disease mechanism and BP1 does not apply.
BP2
CIPA is an autosomal recessive disorder; observation in trans with a pathogenic variant would be expected for affected individuals.
BP4
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.
BP5
No data are available showing this variant occurs in a case with an alternative molecular basis for disease.
BP6
The variant is absent from ClinVar; no reputable source has reported it as benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). REVEL score = 0.683. BayesDel score = 0.0550398.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NTRK1, a receptor tyrosine kinase, is altered by gene fusions in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links