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NTRK1c.1065C>AUncertain significance
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Variant interpretation report

NTRK1 c.1065C>A, p.(Asn355Lys)

NM_002529.3:c.1065C>A NP_002520.2:p.(Asn355Lys) 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

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).

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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. 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 · 4 not met · 16 not assessed · 8 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.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).

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

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.

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.

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).

Met · 1

PM2 ModerateNM_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). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes/genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 4 · evaluated, threshold not reached

PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.372 (intermediate
  • below pathogenic threshold).
  • BayesDel: -0.315 (benign-leaning).
  • SpliceAI max delta: 0.00 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BA1 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%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 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%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.372 (intermediate
  • not benign).
  • BayesDel: -0.315 (benign-leaning).
  • SpliceAI max delta: 0.00.
Sources
revelbayesdelspliceai ↗

Not assessed · 16 · no assessment recorded

PS1 No evidence of a different nucleotide change at codon 355 producing the same p.Asn355Lys missense that has been previously classified as pathogenic. Details ▾Hide ▴
Still missing
  • No known alternate nucleotide substitution resulting in p.Asn355Lys with a pathogenic classification.
PS2 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. Details ▾Hide ▴
Still missing
  • No de novo reports found in ClinVar
  • literature
  • or variant databases.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional data available.
Still missing
  • No dedicated functional analysis of p.Asn355Lys in validated assays (e.g.
  • NGF-dependent autophosphorylation
  • cell survival assays).
Sources
oncokb ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result
  • variant absent from ClinVar.
Still missing
  • No affected proband counts available
  • variant not present in ClinVar.
Sources
clinvar ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Residue 355 is in the LRRCT domain per UniProt annotation
  • but domain-level missense constraint metrics are not available in the case evidence.
Still missing
  • No gnomAD domain-level missense constraint data (observed/expected ratio
  • missense Z-score) for the NTRK1 LRRCT domain.
PM6 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. Details ▾Hide ▴
Still missing
  • No presumed de novo cases reported in ClinVar or literature.
PP1 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. Details ▾Hide ▴
Still missing
  • No family cosegregation studies mentioning this variant.
PP2 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. Details ▾Hide ▴
Evidence considered
  • HCI prior not found for NTRK1
  • no gene-level missense constraint data available.
Still missing
  • No HCI prior or gnomAD gene-level missense Z-score available to assess rate of benign missense variation in NTRK1.
PP4 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. Details ▾Hide ▴
Still missing
  • No patient phenotype data provided.
PP5 The variant is absent from ClinVar, and no reputable source (e.g., clinical diagnostic laboratory, expert panel) has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: variant absent
  • no reputable source classification available.
Sources
clinvar ↗
BS2 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. Details ▾Hide ▴
Still missing
  • No reports of healthy adult carriers of this variant.
BS3 No well-established functional studies demonstrating that p.Asn355Lys has no damaging effect on protein function were identified. Details ▾Hide ▴
Still missing
  • No functional assays demonstrating normal NTRK1 function for p.Asn355Lys.
BS4 No families were identified in which NM_002529.3:c.1065C>A fails to segregate with disease (i.e., non-segregation data). Details ▾Hide ▴
Still missing
  • No segregation data available.
BP2 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. Details ▾Hide ▴
Still missing
  • No unaffected carriers with pathogenic variant in trans reported.
BP5 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. Details ▾Hide ▴
Still missing
  • No data on variant co-occurrence with an alternate molecular diagnosis.
BP6 The variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: variant absent
  • no benign classification available.
Sources
clinvar ↗
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
  • Missense substitution c.1065C>A in exon 8
  • variant_bucket=other
  • apply_generic_pvs1_framework=false
  • gene-level LoF mechanism supported but variant is not a null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessmentpvs1_gene_context3020133630717682385811213321949338763089
PM3 N/AExplicitly skipped per adjudication instructions; not in the only-assess list. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AVariant is a single-nucleotide substitution, not an in-frame deletion/insertion or stop-loss variant. PM4 does not apply. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue candidates from ClinVar
  • 0 expert-panel P/LP candidates.
Sources
pm5_candidates
BP1 N/ACongenital 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. Details ▾Hide ▴
Evidence considered
  • NTRK1 CIPA is caused by both missense and truncating variants
  • missense is a common disease mechanism.
Sources
30201336
BP3 N/AVariant is a single-nucleotide substitution, not an in-frame deletion or insertion in a repetitive region. BP3 does not apply. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is restricted to synonymous variants.
PS5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found no same-residue pathogenic comparator variants.
Sources
pm5_candidates

Identifiers

Gene
NTRK1
Transcript
NM_002529.3
Coding (HGVS c.)
NM_002529.3:c.1065C>A
Protein (HGVS p.)
NP_002520.2:p.(Asn355Lys)
GRCh38
chr1:156873847 C>A
GRCh37
chr1:156843639 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 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -14 bp
0.000
SpliceAI acceptor gainat -351 bp
0.000
SpliceAI donor lossat +112 bp
0.000
SpliceAI donor gainat -45 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.372
BayesDel
-0.315

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.372 (intermediate
  • below pathogenic threshold).
  • BayesDel: -0.315 (benign-leaning).
  • SpliceAI max delta: 0.00 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.372 (intermediate
  • not benign).
  • BayesDel: -0.315 (benign-leaning).
  • SpliceAI max delta: 0.00.
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is restricted to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.372. BayesDel score = -0.315045.

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 0.000 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.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.372. BayesDel score = -0.315045.

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.