About NTRK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK1 c.737C>T, p.(Ser246Phe)
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
PM2Moderate
PM2 · moderate
NM_002529.3:c.737C>T is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (1/1,614,010 alleles, overall AF=6.20×10⁻⁷; highest subpopulation AF=1.10×10⁻⁵ in South Asian, 1/91,076 alleles). The total population allele frequency is well below the 0.1% threshold for PM2 in a non-VCEP framework.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest p.(Ser246Phe) does not have a deleterious effect. REVEL score is 0.132 (below the 0.5 pathogenic threshold), BayesDel score is -0.415 (consistent with a benign prediction), and SpliceAI max delta score is 0.01 (no predicted splicing impact). All available in silico tools are concordant in predicting a non-damaging effect.
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, BP4 supporting benign; combination = 1 moderate + 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
1 / 1,614,010 alleles
gnomAD v4.1: 1 / 1,614,010 alleles. Recorded AF 6.19575e-07. Recorded homozygote count 0.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV62325297, 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: 2 met · 20 not met · 1 not assessed · 3 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.737C>T (p.Ser246Phe) is a missense variant in NTRK1, a gene associated with autosomal recessive congenital insensitivity to pain with anhidrosis (CIPA).
This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (1/1,614,010 alleles; overall AF=6.20×10⁻⁷; highest subpopulation AF=1.10×10⁻⁵ in South Asian), satisfying PM2 at moderate strength.
Multiple in silico tools predict a benign effect: REVEL score of 0.132, BayesDel score of -0.415, and SpliceAI max delta of 0.01. These support BP4 at supporting benign strength.
This missense variant is not eligible for PVS1 as it does not fall into the null-variant buckets of nonsense, frameshift, or canonical splice site variants per ClinGen SVI PVS1 recommendations (PMC6185798).
No functional studies, de novo reports, segregation data, case-control data, or ClinVar classifications exist for this variant. No publications mention NM_002529.3:c.737C>T.
The evidence profile consists of PM2 (moderate) and BP4 (supporting benign). Under generic ACMG/AMP 2015 combination rules, this combination does not meet the threshold for pathogenic, likely pathogenic, benign, or likely benign classification, and the variant therefore remains a variant of uncertain significance (VUS).
No criteria match.
Met · 2
PM2 ModerateNM_002529.3:c.737C>T is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (1/1,614,010 alleles, overall AF=6.20×10⁻⁷; highest subpopulation AF=1.10×10⁻⁵ in South Asian, 1/91,076 alleles). The total population allele frequency is well below the 0.1% threshold for PM2 in a non-VCEP framework. Details ▾Hide ▴
Evidence considered
- gnoMAD v2.1: absent. gnomAD v4.1: 1/1
- 614
- 010 alleles (AF=6.20×10⁻⁷
- 0.000062%). Highest subpopulation AF South Asian = 1.10×10⁻⁵ (0.0011%).
Sources
BP4 SupportingMultiple lines of computational evidence suggest p.(Ser246Phe) does not have a deleterious effect. REVEL score is 0.132 (below the 0.5 pathogenic threshold), BayesDel score is -0.415 (consistent with a benign prediction), and SpliceAI max delta score is 0.01 (no predicted splicing impact). All available in silico tools are concordant in predicting a non-damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.132. BayesDel: -0.415. SpliceAI: 0.01. All in silico tools predict a benign/neutral effect.
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No alternate nucleotide change at codon 737 resulting in the same p.(Ser246Phe) amino acid change has been established as pathogenic. The variant is absent from ClinVar, and no literature reports an alternate nucleotide substitution producing the same protein change. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no known pathogenic variant at this codon with the same amino acid change.
Still missing
- No ClinVar or literature data on alternate nucleotide changes at c.737 producing p.Ser246Phe.
Sources
PS2 No de novo observation has been reported for NM_002529.3:c.737C>T. No publications were identified that describe a de novo occurrence of this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No parental testing or de novo reports are available for this variant.
PS3 No functional studies have been identified for p.(Ser246Phe) or for a systematically characterized range that includes residue 246. OncoKB classifies this variant as 'Unknown Oncogenic Effect.' The COSMIC somatic count (n=1) does not constitute functional evidence. No publications reported experimental characterization of this variant. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. COSMIC: n=1 somatic observation
- not functional data. No variant-specific functional studies in literature.
Still missing
- No in vitro or in vivo functional studies for p.Ser246Phe or a characterized range including this residue.
Sources
PS4 This variant is absent from ClinVar and no affected individuals have been reported in the literature with NM_002529.3:c.737C>T. The single COSMIC entry is somatic and does not contribute to germline PS4. No case-control or cohort data are available. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. COSMIC n=1 is somatic
- not germline. No affected individuals reported.
Still missing
- No germline case-level data for this variant.
Sources
PM1 Residue 246 in NTRK1 is not located in a statistically significant mutational hotspot per cancerhotspots.org. While NTRK1 has a well-characterized functional architecture (extracellular LRR domains, transmembrane domain, tyrosine kinase domain), no domain-level characterization specific to the region containing p.Ser246 was identified in the case evidence that would unambiguously establish it as a critical functional domain with an absence of benign variation. Details ▾Hide ▴
Evidence considered
- Not in a statistically significant hotspot (cancerhotspots.org). Position 246 is in the extracellular domain
- no domain-specific characterization in case materials to support PM1.
Still missing
- No domain-level functional characterization of the region containing p.Ser246 in the case evidence.
PM6 No de novo observation has been reported for NM_002529.3:c.737C>T in any publication or database. De novo occurrence without confirmation of paternity/maternity could not be assessed. Details ▾Hide ▴
Evidence considered
- No de novo reports for this variant.
Still missing
- No de novo data for this variant.
PP1 No co-segregation data are available for NM_002529.3:c.737C>T. No family studies reporting this variant were identified. Details ▾Hide ▴
Evidence considered
- No co-segregation or family data available.
Still missing
- No segregation analysis for this variant.
PP3 Multiple in silico tools do not support a deleterious effect for p.(Ser246Phe). REVEL score is 0.132 (below the 0.5 pathogenic threshold), and BayesDel score is -0.415 (consistent with a benign prediction). SpliceAI max delta score is 0.01, indicating no predicted splicing impact. No HCI prior probability is available for NTRK1. No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.132 (not deleterious). BayesDel: -0.415 (benign). SpliceAI max delta: 0.01 (no splice impact).
Sources
PP4 No patient phenotype or clinical data are available for NM_002529.3:c.737C>T. The variant is absent from ClinVar and no case reports describe the phenotype of individuals harboring this variant. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available.
Still missing
- No clinical phenotype data for carriers of this variant.
PP5 NM_002529.3:c.737C>T is absent from ClinVar and has not been reported as pathogenic by any reputable source. No ClinVar submissions, expert panel reviews, or published classifications are available for this variant. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. No reputable source has classified this variant as pathogenic.
Sources
BA1 The allele frequency of NM_002529.3:c.737C>T in gnomAD v4.1 is 6.20×10⁻⁷ (0.000062%), far below the 1% non-VCEP BA1 threshold. The highest subpopulation frequency is 1.10×10⁻⁵ (0.0011%) in the South Asian population, also well below 1%. Details ▾Hide ▴
Evidence considered
- Overall AF: 6.20×10⁻⁷ (0.000062%). Highest subpopulation AF (South Asian): 1.10×10⁻⁵ (0.0011%). Both << 1% BA1 threshold.
Sources
BS1 The allele frequency of NM_002529.3:c.737C>T is 6.20×10⁻⁷ (0.000062%), far below the 0.3% non-VCEP BS1 threshold. The highest subpopulation frequency is 1.10×10⁻⁵ (0.0011%), also well below 0.3%. Details ▾Hide ▴
Evidence considered
- Overall AF: 6.20×10⁻⁷ (0.000062%). Highest subpopulation AF: 1.10×10⁻⁵ (0.0011%). Both << 0.3% BS1 threshold.
Sources
BS2 No homozygous individuals have been observed in gnomAD v2.1 or v4.1 for NM_002529.3:c.737C>T. No observations in trans with a known pathogenic NTRK1 variant have been reported. BS2 criteria are not satisfied. Details ▾Hide ▴
Evidence considered
- No homozygotes in gnomAD. No trans observations with known pathogenic variants.
Sources
BS3 No well-established functional studies demonstrate a neutral or non-damaging effect for p.(Ser246Phe). No publications report experimental characterization of this variant. OncoKB reports 'Unknown Oncogenic Effect.' Details ▾Hide ▴
Evidence considered
- No functional studies demonstrating a benign effect for this variant.
Still missing
- No functional data for p.Ser246Phe.
Sources
BS4 No segregation data are available for NM_002529.3:c.737C>T. Lack of segregation in affected family members cannot be evaluated. Details ▾Hide ▴
Evidence considered
- No segregation or family data available.
Still missing
- No family/segregation data for this variant.
BP1 NTRK1 is associated with CIPA, and both missense and truncating variants are established disease mechanisms. Over 105 mutations have been reported, including many missense variants. BP1 is applicable only when a gene's disease is caused primarily by truncating variants, which is not the case for NTRK1. Details ▾Hide ▴
Evidence considered
- Both missense and truncating variants cause CIPA. Missense is a recognized disease mechanism for NTRK1.
BP2 BP2 applies to observation in trans with a pathogenic variant in a fully penetrant dominant disorder. CIPA is an autosomal recessive disorder, and no trans observations are available for this variant. BP2 criteria are not satisfied. Details ▾Hide ▴
Evidence considered
- CIPA is autosomal recessive. No trans observations available. BP2 is for dominant disorders.
BP5 No case has been reported in which NM_002529.3:c.737C>T was found in an individual with an alternate molecular basis for disease. BP5 cannot be evaluated without such data. Details ▾Hide ▴
Evidence considered
- No case-level data with alternative molecular diagnosis available.
Still missing
- No case with alternative molecular basis identified.
BP6 NM_002529.3:c.737C>T is absent from ClinVar and has not been reported as benign by any reputable source. No ClinVar submissions or published classifications describe this variant as benign. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. No reputable source has classified this variant as benign.
Sources
PS5 No segregation or family history data are available for NM_002529.3:c.737C>T. No publications report this variant in a familial context. Details ▾Hide ▴
Evidence considered
- No family or segregation data available.
Still missing
- No segregation analysis or family studies for this variant.
Not assessed · 1 · no assessment recorded
PP2 NTRK1 is associated with CIPA (congenital insensitivity to pain with anhidrosis), an autosomal recessive disorder, and loss-of-function missense variants are a recognized disease mechanism. However, no gene-level missense constraint metrics (e.g., Z-score, gnomAD missense constraint) were available in the case materials to evaluate whether NTRK1 has a low rate of benign missense variation. PP2 cannot be reliably assessed without these metrics. Details ▾Hide ▴
Evidence considered
- NTRK1 loss-of-function is a known CIPA mechanism. Missense constraint data not available in case materials.
Still missing
- Missing gene-level missense constraint metrics (gnomAD missense Z-score or equivalent).
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002529.3:c.737C>T is a missense variant (p.Ser246Phe) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- not eligible for PVS1 null-variant framework.
Sources
PM5 N/ANo same-residue ClinVar comparator variants were identified at codon 246 of NTRK1. PM5 candidate harvesting returned zero candidates, and the automatic PM5 pipeline could not establish classic same-residue comparator semantics. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic missense comparators found in ClinVar at codon 246.
BP7 N/ANM_002529.3:c.737C>T is a missense variant (p.Ser246Phe), not a synonymous/silent variant. BP7 is only applicable to synonymous variants that do not affect splicing. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
Identifiers
- Gene
- NTRK1
- Transcript
- NM_002529.3
- Coding (HGVS c.)
- NM_002529.3:c.737C>T
- Protein (HGVS p.)
- NP_002520.2:p.(Ser246Phe)
- GRCh38
- chr1:156871642 C>T
- GRCh37
- chr1:156841434 C>T
- COSMIC
- COSV62325297
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
1 / 1,614,010 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,010 alleles · 0 hom
| South Asian1 / 91,076 | 1.1e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19575e-07; MAF= 0.00006%, 1/1614010 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09798e-05; MAF= 0.00110%, 1/91076 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.132
- BayesDel
- -0.415
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest p.(Ser246Phe) does not have a deleterious effect. REVEL score is 0.132 (below the 0.5 pathogenic threshold), BayesDel score is -0.415 (consistent with a benign prediction), and SpliceAI max delta score is 0.01 (no predicted splicing impact). All available in silico tools are concordant in predicting a non-damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.132. BayesDel: -0.415. SpliceAI: 0.01. All in silico tools predict a benign/neutral effect.
Sources
PP3 Multiple in silico tools do not support a deleterious effect for p.(Ser246Phe). REVEL score is 0.132 (below the 0.5 pathogenic threshold), and BayesDel score is -0.415 (consistent with a benign prediction). SpliceAI max delta score is 0.01, indicating no predicted splicing impact. No HCI prior probability is available for NTRK1. No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.132 (not deleterious). BayesDel: -0.415 (benign). SpliceAI max delta: 0.01 (no splice impact).
Sources
BP7 N/ANM_002529.3:c.737C>T is a missense variant (p.Ser246Phe), not a synonymous/silent variant. BP7 is only applicable to synonymous variants that do not affect splicing. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.132. BayesDel score = -0.415422.
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
1 / 1,614,010 recorded alleles
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.737C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-156841434-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-156871642-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-156871642-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002529.3%3Ac.737C…
- OncoKB ↗www.oncokb.org/gene/NTRK1/S246F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=184506187
- 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
This variant is present in gnomAD v4.1 (AF= 6.19575e-07; MAF= 0.00006%, 1/1614010 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09798e-05; MAF= 0.00110%, 1/91076 alleles, homozygotes = 0).
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 = 0.132. BayesDel score = -0.415422.
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; COSV62325297, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.