About NTRK3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK3 c.1795C>G, p.(His599Asp)
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
PP3Supporting
PP3 · supporting
REVEL score 0.937 predicts a deleterious effect on protein function. BayesDel additive score 0.387 is ambiguous (below the typical deleterious threshold). SpliceAI max delta score 0.00 indicates no predicted splicing impact. REVEL alone provides one line of computational evidence supporting pathogenicity; the conflicting/ambiguous BayesDel score precludes upgrading PP3 to moderate strength.
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: PP3 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.
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
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. NTRK3, a receptor tyrosine kinase, is altered by gene fusion 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: 1 met · 19 not met · 3 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_001012338.2:c.1795C>G (p.His599Asp) is a missense variant in NTRK3. It is absent from ClinVar and no publications describe this variant. Computational evidence (REVEL 0.937) supports a deleterious effect at supporting strength (PP3).
PVS1 is not applicable as this is a missense variant. PM5 is not applicable as no same-residue pathogenic comparator exists. PM2, BA1, and BS1 could not be assessed due to gnomAD v2/v4 data unavailability (query timeout). No functional, segregation, case-control, or de novo data exist.
With only PP3 at supporting strength and no other pathogenic criteria met, the variant does not reach even the lowest Likely Pathogenic threshold (1 Moderate + 4 Supporting or equivalent). It cannot be classified as Benign or Likely Benign either, as no benign criteria are met. The appropriate classification is Variant of Uncertain Significance (VUS).
No criteria match.
Met · 1
PP3 SupportingREVEL score 0.937 predicts a deleterious effect on protein function. BayesDel additive score 0.387 is ambiguous (below the typical deleterious threshold). SpliceAI max delta score 0.00 indicates no predicted splicing impact. REVEL alone provides one line of computational evidence supporting pathogenicity; the conflicting/ambiguous BayesDel score precludes upgrading PP3 to moderate strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.937 (deleterious prediction).
- BayesDel additive: 0.387 (ambiguous).
- SpliceAI max delta: 0.00 (no splice effect).
Still missing
- No HCI prior score available for independent corroboration.
- BayesDel score is ambiguous and does not independently support a deleterious interpretation.
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No alternative pathogenic missense variant at the same amino acid position (His599) has been reported. The variant is absent from ClinVar and no literature describes a different pathogenic missense change at this residue. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no same-residue pathogenic comparator identified.
Sources
PS2 No de novo occurrence data available for this variant. No publications report a confirmed de novo observation of NM_001012338.2:c.1795C>G. Details ▾Hide ▴
Evidence considered
- No de novo studies or case reports identified.
Still missing
- No family-based sequencing or de novo trio data available.
PS3 No functional studies have been performed on this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications with functional data for p.His599Asp were identified. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
- No publications report experimental characterization of this variant.
Still missing
- No functional characterization of p.His599Asp in any experimental system.
Sources
PS4 The variant is absent from ClinVar and no case-control or statistical association data are available. Prevalence of this variant in affected individuals versus controls cannot be assessed. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar — no affected individuals reported.
Still missing
- No case-control or cohort data available.
Sources
PM1 The variant (p.His599Asp) resides in the NTRK3 tyrosine kinase domain (exon 16), but cancerhotspots.org does not identify this residue as a statistically significant mutational hotspot. No published evidence demonstrates that missense variants in this specific region of NTRK3 are enriched in germline disease. The tyrosine kinase domain alone, in the absence of hotspot or domain-specific pathogenic enrichment data, is insufficient to meet PM1. Details ▾Hide ▴
Evidence considered
- Residue H599 not identified as a hotspot at cancerhotspots.org.
- No literature demonstrating pathogenic missense enrichment in this domain for NTRK3 germline disease.
Still missing
- No domain-specific functional characterization linking H599 to disease pathogenesis.
PM6 No de novo occurrence data available for this variant. No publications report a confirmed de novo observation of NM_001012338.2:c.1795C>G. Details ▾Hide ▴
Evidence considered
- No de novo studies or case reports identified.
Still missing
- No de novo confirmation data available.
PP1 No co-segregation data available. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No family or co-segregation data identified.
Still missing
- No pedigree or co-segregation analysis available.
PP2 HCI prior score is unavailable for NTRK3 (gene not supported by the HCI prior database). Without this metric, the rate of benign missense variation in NTRK3 cannot be reliably estimated. Insufficient data to establish PP2. Details ▾Hide ▴
Evidence considered
- HCI prior not found for NTRK3 — cannot assess benign missense constraint.
Still missing
- No constraint metric available for NTRK3.
- No gene-level benign missense rate data.
PP4 No phenotype or clinical data are available for the proband carrying this variant. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No proband phenotype data available.
Still missing
- No clinical or phenotypic data for the proband.
PP5 The variant is absent from ClinVar. No reputable source — including expert panels or clinical testing laboratories — has classified this variant as pathogenic. PP5 requires a reputable source to have reported the variant as pathogenic. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar — no classification available from any submitter.
Sources
BS2 No observation of this variant in a healthy adult control population has been reported. No homozygous or heterozygous observations in unaffected individuals are documented in available databases. Details ▾Hide ▴
Evidence considered
- No observation in healthy control populations reported.
Still missing
- No control population data available.
BS3 No functional studies demonstrating a neutral or benign effect of this variant have been identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No publications report experimental characterization of p.His599Asp. Details ▾Hide ▴
Evidence considered
- No functional studies showing benign/no deleterious effect identified.
- OncoKB: Unknown Oncogenic Effect
- no functional annotation.
Still missing
- No experimental characterization of p.His599Asp.
Sources
BS4 No segregation data demonstrating lack of co-segregation with disease are available. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family-based segregation analysis.
BP1 BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. While NTRK3 loss-of-function is supported as a germline disease mechanism, there is insufficient evidence that NTRK3-related disease is caused primarily by truncating variants to the exclusion of missense variants. Missense variants in receptor tyrosine kinases (including the NTRK family) are well-established as a disease mechanism. Details ▾Hide ▴
Evidence considered
- NTRK3 is a receptor tyrosine kinase
- missense variants are a recognized mechanism in RTK-related disease.
Still missing
- No systematic evidence that NTRK3 disease is exclusively truncating-mediated.
BP2 No observation of this variant in trans with a known pathogenic variant has been reported. Furthermore, NTRK3-related germline disease has not been established as having a recessive inheritance pattern. Details ▾Hide ▴
Evidence considered
- No trans observation reported.
- No established recessive inheritance for NTRK3-related disease.
BP4 REVEL score 0.937 strongly predicts a deleterious effect, directly contradicting BP4. BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. The high REVEL score indicates a predicted damaging effect, not a benign one. Details ▾Hide ▴
Evidence considered
- REVEL: 0.937 (deleterious — contradicts BP4).
- BayesDel: 0.387 (ambiguous).
- SpliceAI: 0.00 (no splice impact).
Sources
BP5 No alternative molecular basis for disease has been identified in this case. BP5 requires that an alternate molecular cause of disease has been found in the proband. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause identified.
Still missing
- No clinical or molecular data available for the proband.
BP6 The variant is absent from ClinVar. No reputable source — including expert panels or clinical testing laboratories — has classified this variant as benign. BP6 requires a reputable source to have reported the variant as benign. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar — no benign classification available from any submitter.
Sources
PS5 No statistically significant association data available. PS5 requires a validated association study demonstrating enrichment of the variant in affected individuals. Details ▾Hide ▴
Evidence considered
- No association studies identified.
Still missing
- No validated association or case-control data.
Not assessed · 3 · no assessment recorded
PM2 gnomAD v2.1 and v4.1 queries timed out during evidence gathering; population frequency data from the major reference databases is unavailable. Absent from gnomAD-Canada v1.0, but this population-specific database alone is insufficient to establish PM2 (<0.1% allele frequency threshold). Reliable assessment of PM2 requires gnomAD v2/v4 population-wide allele frequency data. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD-Canada v1.0 (AC=0).
- gnomAD v2.1/v4.1 data unavailable (query timeout).
Still missing
- gnomAD v2.1 population frequency data unavailable.
- gnomAD v4.1 population frequency data unavailable.
Sources
BA1 gnomAD v2.1 and v4.1 population frequency data are unavailable due to query timeout during evidence gathering. BA1 requires allele frequency >1% in population databases. Without the major reference population data, this criterion cannot be assessed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1/v4.1 data unavailable (query timeout).
Still missing
- gnomAD v2.1 population frequency data unavailable.
- gnomAD v4.1 population frequency data unavailable.
BS1 gnomAD v2.1 and v4.1 population frequency data are unavailable due to query timeout. BS1 requires allele frequency >0.3% in population databases. Absent from gnomAD-Canada v1.0 (AC=0) but this limited population database is insufficient to independently satisfy BS1. Full assessment requires gnomAD v2/v4 data. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD-Canada v1.0 (AC=0).
- gnomAD v2.1/v4.1 data unavailable (query timeout).
Still missing
- gnomAD v2.1 population frequency data unavailable.
- gnomAD v4.1 population frequency data unavailable.
Sources
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.His599Asp). It does not fall into any of the generic PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- Missense variant (p.His599Asp) — not a null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo pathogenic missense variant at the same amino acid residue (His599) has been reported in ClinVar. Per pm5_candidates.json, no same-residue comparator candidates were found. The automatic candidate harvesting confirmed no eligible comparators. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic missense comparator identified in ClinVar.
Sources
pm5_candidatesclinvar ↗
BP7 N/ABP7 is applicable only to synonymous (silent) variants with no predicted splicing impact. NM_001012338.2:c.1795C>G is a missense variant (p.His599Asp) producing an amino acid substitution — it is not synonymous. BP7 is therefore not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant (p.His599Asp) — not synonymous.
Identifiers
- Gene
- NTRK3
- Transcript
- NM_001012338.2
- Coding (HGVS c.)
- NM_001012338.2:c.1795C>G
- Protein (HGVS p.)
- NP_001012338.1:p.(His599Asp)
- GRCh38
- chr15:87933106 G>C
- GRCh37
- chr15:88476337 G>C
Gene diagram
Every interpreted variant in NTRK3, mapped onto the exon structure of NM_001012338.2. Select a row to find it on the plot.
NTRK3NM_001012338.2
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 NTRK3
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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-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.937
- BayesDel
- 0.387
How the predictions were used
PP3 SupportingREVEL score 0.937 predicts a deleterious effect on protein function. BayesDel additive score 0.387 is ambiguous (below the typical deleterious threshold). SpliceAI max delta score 0.00 indicates no predicted splicing impact. REVEL alone provides one line of computational evidence supporting pathogenicity; the conflicting/ambiguous BayesDel score precludes upgrading PP3 to moderate strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.937 (deleterious prediction).
- BayesDel additive: 0.387 (ambiguous).
- SpliceAI max delta: 0.00 (no splice effect).
Still missing
- No HCI prior score available for independent corroboration.
- BayesDel score is ambiguous and does not independently support a deleterious interpretation.
Sources
BP4 REVEL score 0.937 strongly predicts a deleterious effect, directly contradicting BP4. BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. The high REVEL score indicates a predicted damaging effect, not a benign one. Details ▾Hide ▴
Evidence considered
- REVEL: 0.937 (deleterious — contradicts BP4).
- BayesDel: 0.387 (ambiguous).
- SpliceAI: 0.00 (no splice impact).
Sources
BP7 N/ABP7 is applicable only to synonymous (silent) variants with no predicted splicing impact. NM_001012338.2:c.1795C>G is a missense variant (p.His599Asp) producing an amino acid substitution — it is not synonymous. BP7 is therefore not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant (p.His599Asp) — not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.937. BayesDel score = 0.387164.
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 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_001012338.2%3Ac.1795C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/15-88476337-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr15-87933106-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/15-87933106-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001012338.2%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/NTRK3/H599D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NTRK3+c.1795C%3EG
- 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-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 = 0.937. BayesDel score = 0.387164.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NTRK3, a receptor tyrosine kinase, is altered by gene fusion 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.