About NTRK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK1 c.1031G>A, p.(Gly344Glu)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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
PM2Supporting
PM2 · supporting
NM_002529.3:c.1031G>A is absent from all large population databases (gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0), with an allele frequency of 0.00, well below the 0.1% threshold for PM2 in the generic ACMG/AMP framework.
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 supporting; combination = 1 supporting, 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV107439993, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
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 · 23 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002529.3:c.1031G>A (p.Gly344Glu) in NTRK1 is absent from all population databases (gnomAD v2.1, v4.1, Canada v1.0), meeting PM2 at supporting strength.
No additional pathogenic or benign criteria were met. The variant is absent from ClinVar, has no published functional data, and in silico predictors are discordant. COSMIC reports one somatic occurrence (COSV107439993).
Under generic ACMG/AMP 2015 rules, PM2_supporting alone is insufficient for classification. This variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 1
PM2 SupportingNM_002529.3:c.1031G>A is absent from all large population databases (gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0), with an allele frequency of 0.00, well below the 0.1% threshold for PM2 in the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = 0.00).
- Absent from gnomAD v4.1 (AF = 0.00).
- Absent from gnomAD-Canada v1.0 (AF = 0.00).
Sources
Not met · 23 · evaluated, threshold not reached
PS1 No different nucleotide substitution at codon 344 resulting in the same amino acid change (p.Gly344Glu) has been reported as pathogenic. The variant is absent from ClinVar entirely, and no alternative nucleotide change at this codon was identified in any source. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no alternative nucleotide substitution at codon 344 identified.
Still missing
- No ClinVar entries for any variant at codon 344.
Sources
PS2 No de novo observation has been reported for this variant; no parental or trio testing data are available in ClinVar, the literature, or any other evidence source. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No parental testing or trio sequencing data available.
PS3 No variant-specific functional studies were identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no curated functional evidence. No publications with experimental characterization of p.Gly344Glu were found. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect
- no variant-specific functional data in any source.
Still missing
- No functional characterization of p.Gly344Glu in any publication
- no systematic range characterization including residue 344.
Sources
PS4 No case-control or prevalence data are available for this variant. It is absent from ClinVar with no submitted classifications, and no published patient cohorts mention c.1031G>A. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no published patient cohorts.
Still missing
- No affected vs. control allele frequency data.
Sources
PM1 Position Gly344 is not in a statistically significant mutational hotspot per cancerhotspots.org. No ClinGen CSPEC or VCEP framework identifies this residue as a critical functional domain. In the absence of domain-level hotspot characterization specific to this residue, PM1 cannot be applied. Details ▾Hide ▴
Evidence considered
- Not a significant hotspot at cancerhotspots.org
- no CSPEC/VCEP domain-level annotation for residue 344.
Still missing
- No residue-specific domain characterization for Gly344 in NTRK1.
PM5 No different pathogenic missense change at codon 344 was identified. The PM5 candidate collection returned zero candidates at this residue, and ClinVar has no entries for any variant at position Gly344. Details ▾Hide ▴
Evidence considered
- Zero PM5 candidates at residue Gly344
- ClinVar absent for all codon 344 variants.
Still missing
- No comparator pathogenic missense variants at the same residue.
Sources
clinvar ↗pm5_candidates
PM6 No de novo observation has been reported for this variant. No trio sequencing or parental confirmation data are available in any evidence source. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No trio or parental testing data.
PP1 No segregation data are available. No family studies or cosegregation analyses mentioning this variant were identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No segregation or family data.
Still missing
- No family studies or cosegregation data.
PP2 No HCI prior constraint data are available for NTRK1; the gene is not supported in the HCI prior database. Missense constraint cannot be assessed without gene-level benign missense rate data. Details ▾Hide ▴
Evidence considered
- HCI prior data not available for NTRK1.
Still missing
- No gene-level missense constraint data for NTRK1.
PP3 In silico predictors are discordant and do not provide multiple concordant lines of deleterious evidence. REVEL score is borderline at 0.525, BayesDel is benign at 0.160, and SpliceAI predicts no splice impact (max delta 0.00). A single borderline score does not satisfy PP3's requirement for multiple lines of computational evidence. Details ▾Hide ▴
Evidence considered
- REVEL = 0.525 (borderline).
- BayesDel = 0.160 (benign).
- SpliceAI max delta = 0.00 (no splice impact).
Still missing
- Discordant in silico predictions
- no consensus across tools.
Sources
PP4 No patient phenotype or clinical data are available for this case. The variant is absent from ClinVar and no published case reports describe a patient with this specific variant. Details ▾Hide ▴
Evidence considered
- No patient phenotype or clinical history available.
Still missing
- No clinical phenotype data for the proband.
PP5 This variant is absent from ClinVar. No expert panel or reputable source has classified it as pathogenic. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no pathogenic classification by any submitter.
Still missing
- No ClinVar entry for this variant.
Sources
BA1 The variant is absent from gnomAD (AF = 0.00) and does not meet the >1% allele frequency threshold for BA1. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- AF = 0.00.
Sources
BS1 The variant is absent from gnomAD (AF = 0.00) and does not meet the >0.3% allele frequency threshold for BS1 in the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- AF = 0.00.
Sources
BS2 No homozygous observations in healthy adults are reported. The variant is absent from all population databases, providing no data on homozygosity in unaffected individuals. Details ▾Hide ▴
Evidence considered
- No homozygous observations in any database.
Still missing
- No data on homozygous state in healthy individuals.
BS3 No well-established functional studies demonstrating no deleterious effect exist for this variant. OncoKB reports Unknown Oncogenic Effect, and no publications with functional characterization of p.Gly344Glu were identified. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional studies available.
Still missing
- No functional studies showing no damaging effect.
Sources
BS4 No segregation or non-segregation data are available. No family studies involving this variant were identified in any evidence source. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies or non-segregation data.
BP1 NTRK1-associated congenital insensitivity to pain with anhidrosis (CIPA) is caused by both missense and truncating loss-of-function variants. BP1 applies only when a gene's disease mechanism is exclusively through truncating variants, which is not the case for NTRK1. Details ▾Hide ▴
Evidence considered
- CIPA is caused by both missense and truncating NTRK1 variants
- missense variants are a known disease mechanism.
BP2 No phase or trans/cis configuration data are available for this variant. No observation in trans with a known pathogenic variant has been reported. Details ▾Hide ▴
Evidence considered
- No phase or allelic configuration data.
Still missing
- No trans/cis data with pathogenic variants.
BP4 While BayesDel (0.160) and SpliceAI (max delta 0.00) are consistent with a benign interpretation, the REVEL score of 0.525 is borderline pathogenic. This discordance means there are not multiple concordant lines of benign computational evidence required for BP4. Details ▾Hide ▴
Evidence considered
- BayesDel = 0.160 (benign).
- SpliceAI max delta = 0.00 (no splice impact).
- REVEL = 0.525 (borderline pathogenic
- discordant).
Still missing
- Discordant in silico predictions
- not all tools support a benign interpretation.
Sources
BP5 No alternate molecular basis for disease has been identified in this case. No data are available to suggest another causal variant explains the phenotype. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis data available.
Still missing
- No information on whether an alternate cause was excluded.
BP6 This variant is absent from ClinVar. No reputable source has classified it as benign. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign classification by any submitter.
Still missing
- No ClinVar entry for this variant.
Sources
PS5 No different pathogenic missense variant at codon 344 was identified. The PM5 candidate harvest returned zero candidates at this residue, and ClinVar contains no entries for any variant at this position. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue candidates
- ClinVar absent.
Still missing
- No comparator pathogenic variants at codon 344.
Sources
clinvar ↗pm5_candidates
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002529.3:c.1031G>A is a missense variant (p.Gly344Glu) and does not fall into the null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus variants) required for PVS1 application under the ClinGen SVI PVS1 decision framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant p.(Gly344Glu)
- variant bucket = other
- apply_generic_pvs1_framework = false.
Sources
PM3 N/APM3 requires observation in trans with a pathogenic variant for recessive disorders. No phase or trans configuration data are available for this variant. Details ▾Hide ▴
Evidence considered
- No phase data
- variant not observed in trans with a known pathogenic variant.
PM4 N/APM4 applies to protein-length-altering variants (in-frame deletions/insertions, stop-loss). This is a single-nucleotide missense substitution. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a protein-length-altering variant.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This is a single-nucleotide substitution. Details ▾Hide ▴
Evidence considered
- Substitution variant
- not an in-frame indel in a repetitive region.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_002529.3:c.1031G>A is a missense variant (p.Gly344Glu), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Gly344Glu)
- BP7 is restricted to synonymous variants.
Identifiers
- Gene
- NTRK1
- Transcript
- NM_002529.3
- Coding (HGVS c.)
- NM_002529.3:c.1031G>A
- Protein (HGVS p.)
- NP_002520.2:p.(Gly344Glu)
- GRCh38
- chr1:156873813 G>A
- GRCh37
- chr1:156843605 G>A
- COSMIC
- COSV107439993
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…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in NTRK1
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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
Other predictors
- REVEL
- 0.525
- BayesDel
- 0.160
How the predictions were used
PP3 In silico predictors are discordant and do not provide multiple concordant lines of deleterious evidence. REVEL score is borderline at 0.525, BayesDel is benign at 0.160, and SpliceAI predicts no splice impact (max delta 0.00). A single borderline score does not satisfy PP3's requirement for multiple lines of computational evidence. Details ▾Hide ▴
Evidence considered
- REVEL = 0.525 (borderline).
- BayesDel = 0.160 (benign).
- SpliceAI max delta = 0.00 (no splice impact).
Still missing
- Discordant in silico predictions
- no consensus across tools.
Sources
BP4 While BayesDel (0.160) and SpliceAI (max delta 0.00) are consistent with a benign interpretation, the REVEL score of 0.525 is borderline pathogenic. This discordance means there are not multiple concordant lines of benign computational evidence required for BP4. Details ▾Hide ▴
Evidence considered
- BayesDel = 0.160 (benign).
- SpliceAI max delta = 0.00 (no splice impact).
- REVEL = 0.525 (borderline pathogenic
- discordant).
Still missing
- Discordant in silico predictions
- not all tools support a benign interpretation.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_002529.3:c.1031G>A is a missense variant (p.Gly344Glu), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Gly344Glu)
- 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 = 0.525. BayesDel score = 0.160315.
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_002529.3%3Ac.1031G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-156843605-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-156873813-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-156873813-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002529.3%3Ac.1031…
- OncoKB ↗www.oncokb.org/gene/NTRK1/G344E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=184497744
- Cancer hotspots ↗www.cancerhotspots.org/
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 = 0.00). REVEL score = 0.525. BayesDel score = 0.160315.
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 previously been reported in somatic cancers (COSMIC; COSV107439993, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.