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NTRK1c.375C>AUncertain significance
Print report
Variant interpretation report

NTRK1 c.375C>A, p.(Asn125Lys)

NM_002529.3:c.375C>A NP_002520.2:p.(Asn125Lys) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About NTRK1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.190 maximum delta

Recorded SpliceAI maximum delta score: 0.190. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 1 met · 22 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 1

PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles).
  • Absent from gnomAD v4.1 (0 alleles).
  • Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 22 · evaluated, threshold not reached

PS1 No established pathogenic variant with the same amino acid change (p.Asn125Lys) has been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no same-amino-acid pathogenic comparator identified.
Still missing
  • No ClinVar entries exist for this variant or any variant producing p.Asn125Lys.
Sources
clinvar ↗
PS2 No de novo observation with confirmed paternity and maternity has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data available in ClinVar or literature.
Still missing
  • No case-level data available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional studies identified in literature or curated databases.
Still missing
  • No experimental functional characterization of p.Asn125Lys or the surrounding region.
Sources
oncokb ↗
PS4 The variant has not been observed in affected individuals; it is absent from ClinVar, COSMIC, and the published literature. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar and COSMIC
  • no case reports identified.
Still missing
  • No affected individuals identified.
Sources
clinvar ↗
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. 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. Details ▾Hide ▴
Evidence considered
  • Not a statistically significant hotspot
  • no CSPEC-defined critical domain available.
Still missing
  • No CSPEC/VCEP framework defining critical functional domains for NTRK1.
PM6 No de novo observation has been reported for this variant in ClinVar or the published literature. Details ▾Hide ▴
Evidence considered
  • No de novo data available.
Still missing
  • No case-level data available.
PP1 No cosegregation data are available; the variant has not been reported in families with NTRK1-related disease. Details ▾Hide ▴
Evidence considered
  • No family or cosegregation data available.
Still missing
  • No family studies available.
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. Details ▾Hide ▴
Evidence considered
  • HCI Prior not available for NTRK1
  • no missense constraint data evaluated.
Still missing
  • Gene-level missense constraint metrics not available.
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.683 (deleterious-leaning).
  • BayesDel: 0.055 (strongly benign-leaning).
  • SpliceAI max delta: 0.19 (no significant splice impact).
Still missing
  • Contradictory in silico predictions preclude confident PP3 application.
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype data are available to assess whether the clinical presentation is highly specific for NTRK1-related disease. Details ▾Hide ▴
Evidence considered
  • No patient phenotype information available.
Still missing
  • No proband phenotype data.
PP5 The variant is absent from ClinVar; no reputable source has reported it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no reputable source classification available.
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada; allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.0% in all gnomAD populations
  • well below 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from gnomAD; allele frequency does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.0% in all gnomAD populations
  • well below 0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No data are available regarding observation of this variant in healthy adults, whether in trans with a pathogenic variant or at high frequency. Details ▾Hide ▴
Evidence considered
  • No observations in healthy controls with full-penetrance disease.
Still missing
  • No control observations available.
BS3 No well-established functional studies demonstrate a benign effect for this variant. Details ▾Hide ▴
Evidence considered
  • No benign functional evidence identified in literature or curated databases.
Still missing
  • No functional data available.
BS4 No family data are available to assess lack of segregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies or segregation data.
BP1 NTRK1-related CIPA is caused by both missense and truncating mutations; missense variants are an established disease mechanism and BP1 does not apply. Details ▾Hide ▴
Evidence considered
  • NTRK1 missense mutations are a known cause of CIPA
  • truncating variants are not the sole disease mechanism.
BP2 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. Details ▾Hide ▴
Evidence considered
  • NTRK1/CIPA is autosomal recessive
  • no trans-phase observations documented.
Still missing
  • No phase data available.
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. SpliceAI is neutral. Convergence on a benign prediction is not achieved. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.683 (deleterious-leaning
  • contradicts BP4).
  • BayesDel: 0.055 (benign-leaning).
  • SpliceAI: neutral (no splice impact).
Still missing
  • Contradictory in silico predictions preclude confident BP4 application.
Sources
revelbayesdelspliceai ↗
BP5 No data are available showing this variant occurs in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • No alternate molecular cause identified.
Still missing
  • No case-level data.
BP6 The variant is absent from ClinVar; no reputable source has reported it as benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no reputable source benign classification.
Sources
clinvar ↗
PS5 No pathogenic missense variant has been identified at the same codon (Asn125) in ClinVar or the literature to support PS5. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned zero same-residue comparator variants.
Still missing
  • No ClinVar entries for any variant at codon 125.
Sources
clinvar ↗pm5_candidates
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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. Details ▾Hide ▴
Evidence considered
  • Missense substitution — not a null variant
  • generic PVS1 framework does not apply.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant; no phase data available for this variant. Details ▾Hide ▴
Evidence considered
  • No trans-phase observations available for this variant.
PM4 N/APM4 applies to non-repeat indels causing protein-length change; this is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Missense substitution — PM4 is for protein-length-changing indels.
PM5 N/ANo comparator missense variants at the same codon (Asn125) classified as pathogenic were identified in ClinVar; PM5 candidate harvesting returned zero candidates. Details ▾Hide ▴
Evidence considered
  • Zero same-residue comparator variants found.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Missense substitution — BP3 is for in-frame indels.
BP7 N/ABP7 applies to synonymous variants and intronic variants outside splice sites with no predicted splice impact. This is a missense substitution (p.Asn125Lys). Details ▾Hide ▴
Evidence considered
  • Missense substitution — BP7 is for synonymous/intronic variants.

Identifiers

Gene
NTRK1
Transcript
NM_002529.3
Coding (HGVS c.)
NM_002529.3:c.375C>A
Protein (HGVS p.)
NP_002520.2:p.(Asn125Lys)
GRCh38
chr1:156866925 C>A
GRCh37
chr1:156836717 C>A

Gene diagram

Every interpreted variant in NTRK1, mapped onto the exon structure of NM_002529.3. Select a row to find it on the plot.

NTRK1NM_002529.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -15 bp
0.190
SpliceAI acceptor gainat +2 bp
0.000
SpliceAI donor lossat +53 bp
0.170
SpliceAI donor gainat -63 bp
0.000
Pangolin splice lossmagnitude shown
-0.240
Pangolin splice gain
0.010

Other predictors

REVEL
0.683
BayesDel
0.055

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.683 (deleterious-leaning).
  • BayesDel: 0.055 (strongly benign-leaning).
  • SpliceAI max delta: 0.19 (no significant splice impact).
Still missing
  • Contradictory in silico predictions preclude confident PP3 application.
Sources
revelbayesdelspliceai ↗
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. SpliceAI is neutral. Convergence on a benign prediction is not achieved. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.683 (deleterious-leaning
  • contradicts BP4).
  • BayesDel: 0.055 (benign-leaning).
  • SpliceAI: neutral (no splice impact).
Still missing
  • Contradictory in silico predictions preclude confident BP4 application.
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants and intronic variants outside splice sites with no predicted splice impact. This is a missense substitution (p.Asn125Lys). Details ▾Hide ▴
Evidence considered
  • Missense substitution — BP7 is for synonymous/intronic variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). REVEL score = 0.683. BayesDel score = 0.0550398.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.190 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.