About NTRK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK1 c.334C>T, p.(His112Tyr)
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare variant not observed in large population cohorts.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on gene product: REVEL score 0.091 (well below pathogenic threshold), BayesDel score -0.484 (benign range), and SpliceAI max delta score 0.05 (no predicted splicing alteration).
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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
0.050 maximum delta
Recorded SpliceAI maximum delta score: 0.050. 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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV62325616, n = 2 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.
26 criteria with recorded statuses: 2 met · 19 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
PM2 (supporting) is met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, indicating it is rare in the general population.
BP4 (supporting benign) is met: multiple computational predictors (REVEL 0.091, BayesDel -0.484, SpliceAI max delta 0.05) uniformly predict no significant impact on protein function or splicing.
PVS1 is not applicable as this is a missense variant not falling into null-variant categories. No functional studies (PS3/BS3), clinical observations (PS4), de novo data (PS2/PM6), segregation data (PP1/BS4), or ClinVar classifications (PS5/PP5/BP6) are available. With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is indeterminate. Using the generic ACMG/AMP 2015 combination rules (PMID:25741868), this variant is classified as a variant of uncertain significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare variant not observed in large population cohorts. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes). Absent from gnomAD v4.1 (exomes). Absent from gnomAD-Canada v1.0 (genomes).
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product: REVEL score 0.091 (well below pathogenic threshold), BayesDel score -0.484 (benign range), and SpliceAI max delta score 0.05 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
- REVEL: 0.091. BayesDel: -0.484. SpliceAI max delta: 0.05.
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No previously established pathogenic variant with the same amino acid change (H112Y) has been identified at this position in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no pathogenic variant with same amino acid change identified.
Still missing
- No literature reports of a pathogenic H112Y variant.
Sources
PS2 No de novo evidence is available for this variant. No literature reports describe this variant occurring de novo with confirmed maternity and paternity. Details ▾Hide ▴
Still missing
- No parent-of-origin or de novo testing data available.
PS3 No functional studies have been identified for this variant or for a systematically characterized range that includes residue H112. OncoKB reports unknown oncogenic effect. COSMIC somatic observation (n=2) does not constitute experimental functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. COSMIC: COSV62325616
- n=2 somatic
- no functional experimental data.
Still missing
- No in vitro or in vivo functional characterization of H112Y or a systematically characterized range including residue 112.
Sources
PS4 The variant is absent from ClinVar and no patient observations are reported in the literature. No clinical cohort data are available to assess enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar with zero submissions.
Still missing
- No case-control or cohort enrichment data.
Sources
PM1 Residue H112 is not located in a statistically significant mutational hotspot per cancerhotspots.org. No literature evidence specifically characterizes this residue as lying within a critical functional domain where missense variants are established to be pathogenic. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: not a significant hotspot.
Still missing
- No domain-specific functional characterization of residue H112 in the literature.
PM5 No pathogenic missense variant has been identified at the same amino acid residue (H112) with a different amino acid change in ClinVar. Details ▾Hide ▴
Evidence considered
- pm5_candidates found zero same-residue comparator variants.
Still missing
- No ClinVar entries at codon 112 with a different missense change.
Sources
pm5_candidates
PM6 No de novo evidence is available for this variant. No literature reports describe a de novo occurrence with confirmed parentage. Details ▾Hide ▴
Still missing
- No de novo testing data available.
PP1 No segregation data are available for this variant. No family studies have been reported. Details ▾Hide ▴
Still missing
- No co-segregation studies or family pedigrees available.
PP2 While NTRK1 loss-of-function is an established disease mechanism for congenital insensitivity to pain with anhidrosis (CIPA), HCI prior constraint data are not available for NTRK1. Without evidence that the gene has a low rate of benign missense variation, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- NTRK1 LoF is established for CIPA (autosomal recessive)
- but missense constraint metrics (HCI prior
- Z-score) are unavailable.
Still missing
- Missing missense constraint data (HCI prior not found for NTRK1).
Sources
pvs1_gene_context
PP3 Multiple in silico predictors uniformly support a benign interpretation: REVEL score 0.091 (well below 0.5 threshold), BayesDel score -0.484 (negative/benign range), and SpliceAI max delta 0.05 (no predicted splicing impact). No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.091. BayesDel: -0.484. SpliceAI max delta: 0.05.
Sources
PP4 No patient phenotype or clinical data are available to assess whether the proband's phenotype is specific for NTRK1-related disease. Details ▾Hide ▴
Still missing
- No proband phenotype information available.
PP5 This variant is absent from ClinVar; no reputable source has classified it. Details ▾Hide ▴
BS2 No homozygous or hemizygous observations of this variant have been reported in control populations without a disease phenotype. The variant is absent from all gnomAD cohorts. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD
- no homozygous observations possible.
Still missing
- No homozygous/hemizygous control data available.
Sources
BS3 No in vitro or in vivo functional studies have been identified that demonstrate no damaging effect on protein function or splicing for this variant. Details ▾Hide ▴
Still missing
- No functional studies demonstrating benign effect.
BS4 No segregation or family studies are available to assess lack of co-segregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP1 NTRK1-associated congenital insensitivity to pain with anhidrosis (CIPA) is caused by both missense and truncating loss-of-function variants; missense is an established disease mechanism for this gene, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- NTRK1 CIPA is caused by both missense and truncating variants
- missense is a known disease mechanism.
Sources
pvs1_gene_context
BP5 No alternate molecular basis of disease has been identified. This variant has not been observed in a case where an alternative cause was found. Details ▾Hide ▴
Still missing
- No data on alternate molecular diagnoses in carriers.
BP6 No reputable source classifies this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
PS5 This variant is absent from ClinVar; no reputable source has classified it as pathogenic. Details ▾Hide ▴
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.His112Tyr) and does not fall into the ClinGen SVI PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket is 'other'
- apply_generic_pvs1_framework is false per ClinGen SVI PVS1 decision tree (PMC6185798).
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BA1 N/AThe variant is absent from all population databases (allele frequency 0.0%) and does not exceed the 1% BA1 threshold. Details ▾Hide ▴
BS1 N/AThe variant is absent from all population databases (allele frequency 0.0%) and does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
BP2 N/ANo data are available regarding co-occurrence of this variant in trans with a pathogenic NTRK1 variant. Details ▾Hide ▴
Still missing
- No phase or trans-configuration data available.
BP7 N/AThis is a missense variant (c.334C>T, p.His112Tyr), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact and nucleotide-level conservation evidence. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- NTRK1
- Transcript
- NM_002529.3
- Coding (HGVS c.)
- NM_002529.3:c.334C>T
- Protein (HGVS p.)
- NP_002520.2:p.(His112Tyr)
- GRCh38
- chr1:156864774 C>T
- GRCh37
- chr1:156834566 C>T
- COSMIC
- COSV62325616
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
- 0.091
- BayesDel
- -0.484
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product: REVEL score 0.091 (well below pathogenic threshold), BayesDel score -0.484 (benign range), and SpliceAI max delta score 0.05 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
- REVEL: 0.091. BayesDel: -0.484. SpliceAI max delta: 0.05.
Sources
PP3 Multiple in silico predictors uniformly support a benign interpretation: REVEL score 0.091 (well below 0.5 threshold), BayesDel score -0.484 (negative/benign range), and SpliceAI max delta 0.05 (no predicted splicing impact). No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.091. BayesDel: -0.484. SpliceAI max delta: 0.05.
Sources
BP7 N/AThis is a missense variant (c.334C>T, p.His112Tyr), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact and nucleotide-level conservation evidence. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.091. BayesDel score = -0.484273.
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 0.050
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.334C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-156834566-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-156864774-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-156864774-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002529.3%3Ac.334C…
- OncoKB ↗www.oncokb.org/gene/NTRK1/H112Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=184492361
- 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 = 0.05). REVEL score = 0.091. BayesDel score = -0.484273.
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; COSV62325616, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.