About NTRK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK1 c.2004T>A, p.(Asp668Glu)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
PM2 applies when a variant is absent from (or present at extremely low frequency in) population databases. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the generic ACMG threshold of <0.1% allele frequency.
PP3Supporting
PP3 · supporting
PP3 applies when multiple lines of computational evidence support a deleterious effect. The REVEL meta-predictor score of 0.83 (range 0-1) exceeds the commonly used threshold of 0.5 and the more stringent 0.75 threshold, supporting a damaging prediction. BayesDel score is 0.459 (below the 0.5 threshold) and SpliceAI predicts no splicing impact (max delta 0.01). REVEL is a verified meta-predictor incorporating multiple constituent methods; its strong prediction supports PP3 at supporting level despite mixed signals from other predictors.
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, PP3 supporting; combination = 2 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
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The variant NM_002529.3:c.2004T>A (p.Asp668Glu) in NTRK1 is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting PM2 at supporting strength.
REVEL meta-predictor score of 0.83 supports a deleterious effect, meeting PP3 at supporting strength.
No ClinVar entries exist for this variant; no functional data, no de novo reports, no case-control data, and no segregation data are available.
Overall criteria met: PM2 (supporting), PP3 (supporting). Under generic ACMG/AMP 2015 classification rules, two supporting criteria do not reach the threshold for likely pathogenic (requires at least 1 moderate + 4 supporting, or 2 moderate + 2 supporting, or stronger combinations). The variant is classified as a variant of uncertain significance (VUS).
No criteria match.
Met · 2
PM2 SupportingPM2 applies when a variant is absent from (or present at extremely low frequency in) population databases. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the generic ACMG threshold of <0.1% allele frequency. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes + genomes).
- Absent from gnomAD-Canada v1.0 (HostSeq genomes).
Sources
PP3 SupportingPP3 applies when multiple lines of computational evidence support a deleterious effect. The REVEL meta-predictor score of 0.83 (range 0-1) exceeds the commonly used threshold of 0.5 and the more stringent 0.75 threshold, supporting a damaging prediction. BayesDel score is 0.459 (below the 0.5 threshold) and SpliceAI predicts no splicing impact (max delta 0.01). REVEL is a verified meta-predictor incorporating multiple constituent methods; its strong prediction supports PP3 at supporting level despite mixed signals from other predictors. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.83 (deleterious prediction
- verified meta-predictor
- PMID:36413997).
- BayesDel score: 0.459 (below 0.5 threshold).
- SpliceAI max delta: 0.01 (no predicted splice impact).
Still missing
- BayesDel not independently verified
- REVEL is verified.
Sources
Not met · 22 · evaluated, threshold not reached
PS1 PS1 requires a different pathogenic amino acid change at the same codon. No ClinVar entries exist for codon 668 of NTRK1; no pathogenic comparator variant at this residue has been identified. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar.
- No PM5 candidates found at codon 668.
Still missing
- No pathogenic comparator at codon 668 identified in ClinVar or literature.
Sources
PS2 PS2 requires a confirmed de novo occurrence with both maternity and paternity confirmed. No de novo data are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data found in any evidence source.
Still missing
- No parental or de novo testing data available.
PS3 PS3 requires well-established functional studies showing a damaging effect. No variant-specific functional data exist for c.2004T>A (p.Asp668Glu). OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No publications were identified that tested this variant or a systematically characterized range that includes position 668. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional data.
- No PMIDs with functional data for this variant.
- No systematically characterized range including position 668 was identified.
Still missing
- No functional studies available for p.Asp668Glu or a systematically characterized range including amino acid 668.
Sources
PS4 PS4 requires a statistically significant enrichment of the variant in affected individuals compared to controls. No case-control data or prevalence data are available for this variant. Details ▾Hide ▴
Evidence considered
- No case-control or prevalence data available.
Still missing
- No affected-vs-control frequency data.
PM1 PM1 requires location in a mutational hotspot or critical functional domain without benign variation. While p.Asp668Glu lies within the tyrosine kinase domain of NTRK1 (a critical functional domain), residue-specific hotspot analysis (cancerhotspots.org) was negative, and population-level constraint data for this domain are not available under the generic ACMG framework without CSPEC/VCEP guidance. Domain-level PM1 application cannot be confirmed. Details ▾Hide ▴
Evidence considered
- Residue D668 is in the NTRK1 tyrosine kinase domain (exon 15).
- Cancerhotspots.org: no statistically significant hotspot at D668.
- Absent from gnomAD but domain-level benign variation rate unknown.
Still missing
- No CSPEC/VCEP domain-level PM1 rules for NTRK1.
- Domain-wide benign missense variation rate in gnomAD not assessed.
PM5 PM5 requires a different pathogenic missense change at the same amino acid residue. No ClinVar entries and no PM5 candidates were identified at codon 668 (p.Asp668). The PM5 candidate search found zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- No ClinVar entries at codon 668.
- PM5 candidate search: 0 same-residue candidates found.
Still missing
- No pathogenic comparator missense variants at p.Asp668 in ClinVar.
Sources
clinvar ↗pm5_candidates
PM6 PM6 requires a de novo observation without confirmation of maternity and paternity. No de novo data are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data found in any evidence source.
Still missing
- No de novo testing data available.
PP1 PP1 requires cosegregation with disease in multiple affected family members. No cosegregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No cosegregation data available.
Still missing
- No family segregation data.
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. While NTRK1 missense variants are a recognized mechanism in CIPA, population-level constraint metrics (e.g., missense Z-score) are not available in the evidence brief, so the 'low rate of benign missense variation' criterion cannot be confirmed under the generic ACMG framework. Details ▾Hide ▴
Evidence considered
- NTRK1 missense variants are reported in CIPA.
- No missense constraint metrics (Z-score) available.
Still missing
- No gnomAD missense constraint metric (Z-score) extracted in evidence brief.
PP4 PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No patient phenotype or clinical data have been provided for this case. Details ▾Hide ▴
Evidence considered
- No patient phenotype or clinical data available.
Still missing
- No patient phenotype or clinical data provided.
PP5 PP5 requires a reputable source to have classified this variant as pathogenic. The variant is absent from ClinVar; no expert panel or clinical laboratory classification exists. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar.
- No clinical classification available from any source.
Sources
BA1 BA1 requires an allele frequency >5% in population databases. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Sources
BS1 BS1 requires an allele frequency greater than expected for the disorder (>0.3% under generic ACMG). The variant is absent from all population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Sources
BS2 BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. No data show this variant in healthy individuals. Details ▾Hide ▴
Evidence considered
- No evidence of the variant in healthy adults.
Still missing
- No data on variant presence in healthy individuals.
BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. No functional data are available for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies available for p.Asp668Glu.
- OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional data.
Still missing
- No functional data available.
Sources
BS4 BS4 requires lack of segregation with disease in affected family members. No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No segregation data.
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease. NTRK1-related CIPA is caused by both missense and truncating variants; missense variants are a recognized disease mechanism. BP1 does not apply. Details ▾Hide ▴
Evidence considered
- NTRK1 CIPA is caused by both missense and truncating LoF variants.
- Over 105 NTRK1 mutations reported in CIPA including missense variants (PMID:30201336).
Sources
pvs1_gene_context
BP2 BP2 requires observation in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant. No phase data are available for this variant. Details ▾Hide ▴
Evidence considered
- No in trans or in cis observation data.
Still missing
- No phase data available.
BP4 BP4 requires multiple lines of computational evidence to suggest no impact on gene or gene product. REVEL score of 0.83 predicts a damaging effect, contradicting BP4. SpliceAI predicts no splicing impact but this alone is insufficient when a major meta-predictor supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.83 (predicts damaging
- contradicts BP4).
- BayesDel score: 0.459 (borderline).
- SpliceAI max delta: 0.01 (no splice impact).
Sources
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No data on alternate molecular diagnoses are available. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
Still missing
- No data on alternate molecular diagnoses in carriers.
BP6 BP6 requires a reputable source to have classified this variant as benign. The variant is absent from ClinVar; no classification exists. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar.
- No benign classification from any source.
Sources
PS5 PS5 requires a different pathogenic nucleotide change at the same genomic position. No ClinVar entries exist for this nucleotide position (1-156849112-T-A or 1-156879320-T-A), and no PM5 candidates were identified at codon 668. Details ▾Hide ▴
Evidence considered
- No ClinVar entries at this nucleotide position.
- No PM5 candidate variants at codon 668.
Still missing
- No pathogenic comparator at this nucleotide position in ClinVar.
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus). This is a missense variant (c.2004T>A, p.Asp668Glu) and does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a null variant.
- PVS1 variant assessment classified variant as bucket 'other'
- apply_generic_pvs1_framework = false.
Sources
BP7 N/ABP7 is reserved for synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.2004T>A, p.Asp668Glu). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not synonymous.
Identifiers
- Gene
- NTRK1
- Transcript
- NM_002529.3
- Coding (HGVS c.)
- NM_002529.3:c.2004T>A
- Protein (HGVS p.)
- NP_002520.2:p.(Asp668Glu)
- GRCh38
- chr1:156879320 T>A
- GRCh37
- chr1:156849112 T>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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in NTRK1
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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
- 0.830
- BayesDel
- 0.459
How the predictions were used
PP3 SupportingPP3 applies when multiple lines of computational evidence support a deleterious effect. The REVEL meta-predictor score of 0.83 (range 0-1) exceeds the commonly used threshold of 0.5 and the more stringent 0.75 threshold, supporting a damaging prediction. BayesDel score is 0.459 (below the 0.5 threshold) and SpliceAI predicts no splicing impact (max delta 0.01). REVEL is a verified meta-predictor incorporating multiple constituent methods; its strong prediction supports PP3 at supporting level despite mixed signals from other predictors. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.83 (deleterious prediction
- verified meta-predictor
- PMID:36413997).
- BayesDel score: 0.459 (below 0.5 threshold).
- SpliceAI max delta: 0.01 (no predicted splice impact).
Still missing
- BayesDel not independently verified
- REVEL is verified.
Sources
BP4 BP4 requires multiple lines of computational evidence to suggest no impact on gene or gene product. REVEL score of 0.83 predicts a damaging effect, contradicting BP4. SpliceAI predicts no splicing impact but this alone is insufficient when a major meta-predictor supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.83 (predicts damaging
- contradicts BP4).
- BayesDel score: 0.459 (borderline).
- SpliceAI max delta: 0.01 (no splice impact).
Sources
BP7 N/ABP7 is reserved for synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.2004T>A, p.Asp668Glu). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.83. BayesDel score = 0.459299.
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 0.010
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.2004T%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-156849112-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-156879320-T-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-156879320-T-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002529.3%3Ac.2004…
- OncoKB ↗www.oncokb.org/gene/NTRK1/D668E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NTRK1+c.2004T%3EA
- 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 = 0.01). REVEL score = 0.83. BayesDel score = 0.459299.
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.