About NTRK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK1 c.1334G>A, p.(Arg445Lys)
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.1334G>A is absent from all population databases: gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles). The variant has a population allele frequency of 0.0, well below the PM2 threshold of <0.1%.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence predict no deleterious impact: REVEL score 0.277 (pathogenic threshold ≥0.5 not met), BayesDel score -0.176 (pathogenic threshold ≥0.27 not met), and SpliceAI max delta score 0.00 (no splicing impact predicted). All three in silico tools uniformly predict a benign 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
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.
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.
29 criteria with recorded statuses: 2 met · 4 not met · 7 not assessed · 16 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.1334G>A (p.Arg445Lys) is a missense variant in exon 11 of NTRK1.
This variant is absent from all population databases: gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0; PM2 met at moderate strength).
Multiple lines of computational evidence predict a benign effect: REVEL 0.277, BayesDel -0.176, SpliceAI max delta 0.00 (BP4 met at supporting benign strength).
No published literature, ClinVar submissions, or functional studies specific to this variant were identified.
NTRK1 loss-of-function variants cause autosomal recessive congenital insensitivity to pain with anhidrosis (CIPA); missense variants are a known disease mechanism.
Applying generic ACMG/AMP 2015 final classification rules (PMID:25741868): one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) are insufficient to classify as likely pathogenic or likely benign. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 ModerateNM_002529.3:c.1334G>A is absent from all population databases: gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles). The variant has a population allele frequency of 0.0, well below the PM2 threshold of <0.1%. 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 predict no deleterious impact: REVEL score 0.277 (pathogenic threshold ≥0.5 not met), BayesDel score -0.176 (pathogenic threshold ≥0.27 not met), and SpliceAI max delta score 0.00 (no splicing impact predicted). All three in silico tools uniformly predict a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.277 (<0.5 threshold)
- BayesDel: -0.176 (<0.27 threshold)
- SpliceAI: max delta 0.00
Sources
Not met · 4 · evaluated, threshold not reached
PP3 In silico tools uniformly predict a benign effect: REVEL score 0.277 (below the 0.5 threshold for pathogenicity), BayesDel score -0.176 (below the 0.27 threshold), and SpliceAI max delta score 0.00 (no predicted splice impact). Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.277 (benign range)
- BayesDel: -0.176 (benign range)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0.0 does not meet the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.0 in all gnomAD datasets
- BA1 threshold is >1%
Sources
BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0.0 does not meet the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.0 in all gnomAD datasets
- BS1 threshold is >0.3%
Sources
BP1 BP1 applies to missense variants in genes where only truncating variants cause disease. NTRK1-related CIPA is caused by both missense and truncating mutations, as documented in the literature. Therefore, missense variants are an established disease mechanism in NTRK1, and BP1 cannot be applied. Details ▾Hide ▴
Evidence considered
- Published CIPA literature confirms both missense and truncating NTRK1 mutations cause disease
- e.g.
- c.44G>A (p.Trp15*)
- c.1549G>C
- c.2020G>T (p.Asp674Tyr)
Not assessed · 7 · no assessment recorded
PS3 OncoKB reports Unknown Oncogenic Effect for NTRK1 R445K with no variant-specific reviewed functional evidence. No published functional studies of this variant were identified in the literature or curated databases. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence curated
Still missing
- No in vitro or in vivo functional studies of NM_002529.3:c.1334G>A identified
Sources
PS4 This variant is absent from ClinVar and no case-control or cohort studies reporting this variant in affected individuals were identified. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no published case reports identified
Still missing
- No variant-specific prevalence data in affected vs. control populations
PM1 The variant maps to codon 445 within the tyrosine kinase domain of NTRK1, and is absent from population databases (gnomAD). However, no statistically significant mutational hotspot encompasses this residue, and explicit domain-level PM1 criteria (e.g., ClinGen domain constraint data) are not available for NTRK1 in the evidence packet. Details ▾Hide ▴
Evidence considered
- Residue 445 is in the tyrosine kinase domain
- gnomAD absence supports no benign variation at this locus
- not in a statistically significant hotspot
Still missing
- No ClinGen domain-level PM1 annotation or critical functional domain calibration for NTRK1 available
Sources
PP2 NTRK1 is a disease gene for congenital insensitivity to pain with anhidrosis (CIPA), with missense variants reported as a known disease mechanism. However, HCI prior missense constraint data is not available for NTRK1, preventing formal quantification of the rate of benign missense variation required for PP2 application. Details ▾Hide ▴
Evidence considered
- NTRK1 missense variants are a known mechanism in CIPA
- gene is absent from population databases for this variant
Still missing
- HCI prior missense constraint score unavailable for NTRK1
PP4 No patient phenotype or family history data are available for this case. The variant is absent from ClinVar and no clinical case reports were identified. Details ▾Hide ▴
Still missing
- No patient phenotype data available for phenotype-specificity assessment
BS2 No observations of this variant in healthy adults have been reported. Clinical phenotype data for any carriers are unavailable. Details ▾Hide ▴
Still missing
- No data on observation in healthy adult individuals
BS3 No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of NM_002529.3:c.1334G>A (p.Arg445Lys) were identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional studies identified
Still missing
- No functional studies demonstrating a benign effect of this variant
Sources
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002529.3:c.1334G>A is a missense variant (p.Arg445Lys) in exon 11. It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Per ClinGen SVI PVS1 recommendations (PMC6185798), generic PVS1 framework is not applicable to this variant class. Details ▾Hide ▴
Evidence considered
- Variant class is substitution (missense)
- not a predicted null variant
Sources
PS1 N/ANo alternative nucleotide change at c.1334 resulting in the same p.Arg445Lys amino acid change has been identified in ClinVar or the literature. Details ▾Hide ▴
No further detail was recorded.
PS2 N/ANo de novo observation with confirmed paternity and maternity has been reported for this variant in any available source. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped per user instruction: no evidence relevant to this criterion available. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per user instruction: variant is a substitution, PM4 applies to in-frame deletions/insertions and stop-loss variants. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo pathogenic missense variants at the same residue (Arg445) with a different amino acid change were identified in ClinVar. PM5 candidate harvesting returned zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants identified
- ClinVar has no entries for this residue
Sources
pm5_candidates
PM6 N/ANo de novo observation (without confirmation of paternity and maternity) has been reported for this variant. Details ▾Hide ▴
No further detail was recorded.
PP1 N/ANo co-segregation data are available for this variant. No family studies were identified in the literature or ClinVar. Details ▾Hide ▴
No further detail was recorded.
PP5 N/ANo reputable source (e.g., clinical diagnostic laboratory) has reported NM_002529.3:c.1334G>A as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
BS4 N/ANo segregation data are available for this variant. No family studies involving this variant were identified. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ANo observation of this variant in trans with a known pathogenic NTRK1 variant has been reported. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASkipped per user instruction: variant is a substitution, BP3 applies to in-frame indels in repeat regions. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ANo observation of this variant in a case with an established alternate molecular basis for disease has been reported. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ANo reputable source has classified NM_002529.3:c.1334G>A as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no prior benign classification by any submitter
Sources
BP7 N/ANM_002529.3:c.1334G>A is a missense variant (p.Arg445Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant type is missense
- not synonymous
PS5 N/APS5 is not a standard criterion in the ACMG/AMP 2015 framework (Richards et al., PMID:25741868). No equivalent criterion exists in the generic ACMG/AMP classification rules being applied to this case. Details ▾Hide ▴
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- NTRK1
- Transcript
- NM_002529.3
- Coding (HGVS c.)
- NM_002529.3:c.1334G>A
- Protein (HGVS p.)
- NP_002520.2:p.(Arg445Lys)
- GRCh38
- chr1:156874988 G>A
- GRCh37
- chr1:156844780 G>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
- 0.277
- BayesDel
- -0.176
How the predictions were used
BP4 SupportingMultiple lines of computational evidence predict no deleterious impact: REVEL score 0.277 (pathogenic threshold ≥0.5 not met), BayesDel score -0.176 (pathogenic threshold ≥0.27 not met), and SpliceAI max delta score 0.00 (no splicing impact predicted). All three in silico tools uniformly predict a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.277 (<0.5 threshold)
- BayesDel: -0.176 (<0.27 threshold)
- SpliceAI: max delta 0.00
Sources
PP3 In silico tools uniformly predict a benign effect: REVEL score 0.277 (below the 0.5 threshold for pathogenicity), BayesDel score -0.176 (below the 0.27 threshold), and SpliceAI max delta score 0.00 (no predicted splice impact). Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.277 (benign range)
- BayesDel: -0.176 (benign range)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
BP7 N/ANM_002529.3:c.1334G>A is a missense variant (p.Arg445Lys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant type is missense
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.277. BayesDel score = -0.176181.
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.1334G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-156844780-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-156874988-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-156874988-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002529.3%3Ac.1334…
- OncoKB ↗www.oncokb.org/gene/NTRK1/R445K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NTRK1+c.1334G%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 = 0.00). REVEL score = 0.277. BayesDel score = -0.176181.
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.