About NTRK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK1 c.926C>T, p.(Pro309Leu)
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.926C>T is absent from gnomAD v2.1 (0/246,210 alleles) and gnomAD v4.1 (0 alleles). Under generic ACMG/AMP rules, absence from population databases at an allele frequency below 0.1% supports PM2 at supporting strength for a missense variant without additional corroborating evidence.
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
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/246210 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15518 alleles, homozygotes = 0).
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
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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; COSV62323938, 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.
26 criteria with recorded statuses: 1 met · 16 not met · 0 not assessed · 9 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.926C>T (p.Pro309Leu) in NTRK1 is classified as a Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework.
One supporting pathogenic criterion was met: PM2 (absent from gnomAD v2.1 and v4.1 population databases).
No benign criteria were met. Population absence does not support BA1 (>1%), BS1 (>0.3%), or BS2 (no homozygotes observed). In silico predictions are mixed (REVEL 0.554 damaging; BayesDel 0.172 neutral; SpliceAI 0.00 no splice effect), preventing application of either PP3 or BP4.
Only one supporting-level criterion (PM2) was met, which is insufficient to reach Likely Pathogenic or Likely Benign under the ACMG/AMP 2015 combination rules. The variant remains as Uncertain Significance.
No criteria match.
Met · 1
PM2 SupportingNM_002529.3:c.926C>T is absent from gnomAD v2.1 (0/246,210 alleles) and gnomAD v4.1 (0 alleles). Under generic ACMG/AMP rules, absence from population databases at an allele frequency below 0.1% supports PM2 at supporting strength for a missense variant without additional corroborating evidence. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/246
- 210 alleles (AF=0.000%)
- gnomAD v4.1: absent
Sources
Not met · 16 · evaluated, threshold not reached
PS1 PS1 requires the same amino acid change (Pro309Leu) to have been previously established as pathogenic. The ClinVar record for this exact variant (VariationID 526728) is classified as Uncertain Significance by a single submitter, not Pathogenic. No independent evidence establishes Pro309Leu as a pathogenic change. Details ▾Hide ▴
Evidence considered
- Same amino acid change (Pro309Leu) has only a VUS classification in ClinVar
- not a pathogenic assertion
Sources
PS3 No functional studies have been performed on NM_002529.3:c.926C>T (p.Pro309Leu). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. The single COSMIC entry (COSV62323938, n=1) reflects somatic observation, not experimental functional characterization. No publications with experimental functional data for this variant were identified in the literature pass or among the reviewed papers. Details ▾Hide ▴
Evidence considered
- OncoKB: no variant-specific functional evidence
- COSMIC: 1 somatic observation without functional characterization
Still missing
- No experimental functional studies available for p.Pro309Leu
Sources
PS4 No case-level evidence was identified for this variant. The PS4 screen returned zero qualifying cases. PMIDs 20301726 and 29419974 are GeneReviews overview chapters on NTRK1-related congenital insensitivity to pain — they do not report this specific variant. The single ClinVar submission (SCV000752360, Labcorp/Invitae) does not provide case counts or affected individual data. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 submitter VUS with no case counts
- GeneReviews chapters: no variant-specific case data
- PS4 screen: 0 qualifying cases
Still missing
- No case observations in affected individuals
Sources
PM1 PM1 requires location in a mutational hotspot or well-established critical functional domain without benign variation. Cancerhotspots.org does not identify residue 309 as a statistically significant hotspot. While NTRK1 position 309 lies in the extracellular leucine-rich repeat domain involved in ligand binding, no domain-level mutational constraint data or CSPEC/VCEP domain specification was available to support PM1 application under generic ACMG rules. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue 309 not a significant hotspot
- no CSPEC/VCEP domain specification for NTRK1
Still missing
- No functional domain constraint data or VCEP domain specification available for NTRK1 residue 309
PM5 PM5 requires a different pathogenic missense change at the same amino acid residue (Pro309). No same-residue comparator variants classified as pathogenic or likely pathogenic were identified in ClinVar. The automated PM5 candidate harvest returned zero candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvest: 0 same-residue comparator variants found
- no pathogenic/likely pathogenic variant at Pro309
PP2 PP2 requires a low rate of benign missense variation in the gene with missense variants being a common disease mechanism. While NTRK1 loss-of-function is an established mechanism for congenital insensitivity to pain with anhidrosis (CIPA) and missense variants are observed in CIPA, formal constraint metrics (e.g., gnomAD missense Z-score, HCI prior) were not available for NTRK1 to support application of PP2 under generic ACMG rules. Details ▾Hide ▴
Evidence considered
- NTRK1 LoF mechanism established for CIPA
- but no formal missense constraint metrics available
Still missing
- No gene-level missense constraint metrics (Z-score or HCI prior) available for NTRK1
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.554 (borderline damaging, just above the 0.5 threshold). BayesDel score is 0.172 (neutral-to-benign range). SpliceAI predicts no splice impact (max delta = 0.00). With only one in silico tool suggesting a potentially damaging effect and others indicating neutrality, the evidence does not meet the threshold for multiple lines supporting a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.554 (borderline damaging)
- BayesDel: 0.172 (neutral)
- SpliceAI: max delta 0.00 (no splice effect)
Sources
PP5 PP5 requires a reputable source to have recently reported the variant as pathogenic, with the evidence not available for independent review. The ClinVar classification for NM_002529.3:c.926C>T is Uncertain Significance (VariationID 526728, 1 clinical laboratory, review status: criteria provided, single submitter). This is not a pathogenic assertion and does not meet the 3-star expert panel threshold. The ClinVar-linked PMIDs (20301726, 29419974) are GeneReviews overviews that do not classify this specific variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar VUS (1 submitter
- 1-star)
- GeneReviews chapters: no pathogenic classification for this variant
Sources
BA1 BA1 requires allele frequency >1% in population databases. NM_002529.3:c.926C>T is absent from gnomAD v2.1 (0/246,210 alleles) and gnomAD v4.1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/246
- 210 alleles (AF=0.000%)
- gnomAD v4.1: absent
Sources
BS1 BS1 requires allele frequency >0.3% in population databases. NM_002529.3:c.926C>T is absent from gnomAD v2.1 and v4.1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/246
- 210 alleles (AF=0.000%)
- gnomAD v4.1: absent
Sources
BS2 BS2 requires observation in a healthy adult in a homozygous or hemizygous state (or in trans with a pathogenic variant for dominant disorders). NM_002529.3:c.926C>T has zero homozygotes in gnomAD and no observations in trans with a pathogenic variant have been reported. Details ▾Hide ▴
BS3 BS3 requires well-established functional studies showing no damaging effect on protein function or splicing. No functional studies have been performed on NM_002529.3:c.926C>T (p.Pro309Leu). OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- No functional studies available for p.Pro309Leu
- OncoKB: Unknown Oncogenic Effect
Still missing
- No functional data available
Sources
BP1 BP1 applies when a missense variant occurs in a gene for which only truncating variants are known to cause disease. NTRK1-related congenital insensitivity to pain with anhidrosis (CIPA) is caused by both missense and truncating loss-of-function variants, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- NTRK1 CIPA is caused by both missense and truncating variants
- BP1 is specific to genes where only truncating variants cause disease
BP2 BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for a recessive disorder. No phase information is available for NM_002529.3:c.926C>T. Details ▾Hide ▴
Evidence considered
- No phase information or in-trans/in-cis observations available
Still missing
- No phasing data available
BP4 BP4 requires multiple lines of computational evidence to suggest no impact on the gene or gene product. REVEL score is 0.554 (damaging prediction, above 0.5 threshold), which contradicts a no-impact prediction. BayesDel score is 0.172 (neutral-tending but not strongly benign), and SpliceAI predicts no splice effect (max delta = 0.00). The REVEL result alone prevents BP4 from being met, as there is not consensus among computational tools suggesting a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.554 (damaging
- contradicts no-impact)
- BayesDel: 0.172 (neutral)
- SpliceAI: max delta 0.00 (no splice effect)
Sources
BP6 BP6 requires a reputable source to report the variant as benign with evidence not available for independent review. The ClinVar classification for NM_002529.3:c.926C>T is Uncertain Significance (VariationID 526728, 1 submitter), not benign. No expert panel has classified this variant as benign. Details ▾Hide ▴
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_002529.3:c.926C>T is a missense change (p.Pro309Leu) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required by the ClinGen SVI PVS1 decision framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant does not qualify for PVS1 null-variant framework
Sources
PS2 N/ANo de novo evidence is available. No parental sequencing data or de novo reports exist in the case materials for NM_002529.3:c.926C>T. Details ▾Hide ▴
Still missing
- No parental or trio sequencing data available
PM6 N/ANo de novo observations exist for NM_002529.3:c.926C>T. PM6 requires an assumed or confirmed de novo event with no confirmation of paternity and maternity, which is unavailable for this variant. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 N/ANo segregation data is available. PP1 requires co-segregation of the variant with disease in multiple affected family members, which has not been assessed for NM_002529.3:c.926C>T. Details ▾Hide ▴
Still missing
- No family segregation data available
PP4 N/ANo patient phenotype information was provided in the case materials. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient phenotype data available in case materials
BS4 N/ANo segregation data is available. BS4 requires lack of segregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available
BP5 N/ABP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data is available in the case materials. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_002529.3:c.926C>T is a missense variant (p.Pro309Leu), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous — BP7 not applicable
PS5 N/APS5 is not a standard criterion in the ACMG/AMP 2015 variant interpretation framework. There is no applicable evidence pathway for this criterion under the generic ACMG fallback rules. Details ▾Hide ▴
Evidence considered
- Not a standard ACMG/AMP 2015 criterion
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- NTRK1
- Transcript
- NM_002529.3
- Coding (HGVS c.)
- NM_002529.3:c.926C>T
- Protein (HGVS p.)
- NP_002520.2:p.(Pro309Leu)
- GRCh38
- chr1:156873708 C>T
- GRCh37
- chr1:156843500 C>T
- ClinVar
- 526728
- COSMIC
- COSV62323938
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
0 / 246,210 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v2.1
AF 0 · 0 / 246,210 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/246210 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15518 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.554
- BayesDel
- 0.172
How the predictions were used
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.554 (borderline damaging, just above the 0.5 threshold). BayesDel score is 0.172 (neutral-to-benign range). SpliceAI predicts no splice impact (max delta = 0.00). With only one in silico tool suggesting a potentially damaging effect and others indicating neutrality, the evidence does not meet the threshold for multiple lines supporting a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.554 (borderline damaging)
- BayesDel: 0.172 (neutral)
- SpliceAI: max delta 0.00 (no splice effect)
Sources
BP4 BP4 requires multiple lines of computational evidence to suggest no impact on the gene or gene product. REVEL score is 0.554 (damaging prediction, above 0.5 threshold), which contradicts a no-impact prediction. BayesDel score is 0.172 (neutral-tending but not strongly benign), and SpliceAI predicts no splice effect (max delta = 0.00). The REVEL result alone prevents BP4 from being met, as there is not consensus among computational tools suggesting a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.554 (damaging
- contradicts no-impact)
- BayesDel: 0.172 (neutral)
- SpliceAI: max delta 0.00 (no splice effect)
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_002529.3:c.926C>T is a missense variant (p.Pro309Leu), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous — BP7 not applicable
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.554. BayesDel score = 0.172357.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 20301726 ↗NTRK1 Congenital Insensitivity to Pain with Anhidrosis.Adam MP et al. · 1993GeneReviews chapter summarizing NTRK1-related congenital insensitivity to pain with anhidrosis (CIPA). Provides gene-level overview of NTRK1 mutations and CIPA clinical features but does not discuss NM_002529.3:c.926C>T (p.Pro309Leu).Does not name this variant
-
PMID 29419974 ↗Congenital Insensitivity to Pain Overview.Adam MP et al. · 1993GeneReviews overview chapter on congenital insensitivity to pain. Provides general clinical and genetic context for NTRK1-related disorders but does not mention NM_002529.3:c.926C>T (p.Pro309Leu).Does not name this variant
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
1 Uncertain significance
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/variation/526728/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-156843500-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-156873708-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-156873708-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002529.3%3Ac.926C…
- OncoKB ↗www.oncokb.org/gene/NTRK1/P309L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=184503047
- 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
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/246210 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15518 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 526728)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.554. BayesDel score = 0.172357.
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; COSV62323938, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.