About NTRK3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK3 c.1730C>T, p.(Pro577Leu)
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
This variant is present at extremely low frequency in gnomAD: v2.1 AF = 7.97e-6 (2/251,054 alleles, 0 homozygotes) and v4.1 AF = 1.24e-6 (2/1,614,122 alleles), with grpmax FAF = 9.58e-6. Both allele frequencies are well below the 0.1% threshold for PM2.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no deleterious impact. BayesDel score is -0.141 (benign), SpliceAI predicts no splicing alteration (max delta = 0.00), and REVEL score is 0.541 (only borderline above the pathogenic threshold). The preponderance of in silico evidence supports a benign interpretation.
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
2 / 1,614,122 alleles
gnomAD v4.1: 2 / 1,614,122 alleles. Recorded AF 1.23906e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96641e-06; MAF= 0.00080%, 2/251054 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.78402e-05; MAF= 0.00578%, 2/34578 alleles, homozygotes = 0); grpmax FAF= 9.58e-06.
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. 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: 2 met · 22 not met · 0 not assessed · 2 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.1730C>T (p.Pro577Leu) is present at extremely low frequency in gnomAD (v2.1 AF = 7.97e-6, v4.1 AF = 1.24e-6), meeting PM2 at supporting level.
Multiple in silico tools predict a benign effect: BayesDel score is -0.141 (benign), SpliceAI predicts no splicing impact (delta = 0.00), and REVEL is borderline at 0.541, meeting BP4 at supporting benign level.
No other pathogenic or benign criteria were met. The variant is absent from ClinVar, has no functional data (OncoKB: Unknown Oncogenic Effect), is not in a mutational hotspot, and was not identified in any variant-specific literature.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient to classify this variant as either likely pathogenic or likely benign. The variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines (PMID:25741868).
No criteria match.
Met · 2
PM2 SupportingThis variant is present at extremely low frequency in gnomAD: v2.1 AF = 7.97e-6 (2/251,054 alleles, 0 homozygotes) and v4.1 AF = 1.24e-6 (2/1,614,122 alleles), with grpmax FAF = 9.58e-6. Both allele frequencies are well below the 0.1% threshold for PM2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF = 7.97e-6
- 2/251
- 054 alleles
- 0 homozygotes
- grpmax FAF = 9.58e-6
- gnomAD v4.1: AF = 1.24e-6
- 2/1
- 614
- 122 alleles
- grpmax FAF = 5.53e-6
Sources
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact. BayesDel score is -0.141 (benign), SpliceAI predicts no splicing alteration (max delta = 0.00), and REVEL score is 0.541 (only borderline above the pathogenic threshold). The preponderance of in silico evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.141 (benign prediction)
- SpliceAI: max delta = 0.00 (no splicing impact)
- REVEL: 0.541 (borderline
- does not independently override benign signals)
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No ClinVar entry exists for a pathogenic variant with the same amino acid change (p.Pro577Leu) at this position. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no same-amino-acid pathogenic comparator identified.
Sources
PS2 No de novo occurrence data are available for this variant in any curated source. Details ▾Hide ▴
Evidence considered
- No de novo data identified in ClinVar
- literature
- or evidence sources.
Still missing
- No parental testing or de novo reports available.
PS3 No variant-specific functional studies were identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' and the literature search returned no experimental functional data for NM_001012338.2:c.1730C>T or p.Pro577Leu. Details ▾Hide ▴
Evidence considered
- OncoKB reports no curated functional evidence for this variant.
Still missing
- No experimental functional studies available for this exact variant or a systematically characterized range that includes position 577.
Sources
PS4 No case-control or cohort data are available to support enrichment of this variant in affected individuals. Details ▾Hide ▴
Evidence considered
- No case-control or cohort studies identified.
Still missing
- No affected vs. control population data.
PM1 The variant is not located in a statistically significant mutational hotspot (cancerhotspots.org) and the missense change p.Pro577Leu does not remove or truncate the tyrosine kinase domain; domain-level PM1 is not supported without residue-specific functional characterization. Details ▾Hide ▴
Evidence considered
- Residue 577 is not a significant hotspot
- variant is a missense substitution within the kinase domain without demonstrated domain disruption.
PM5 No same-residue pathogenic comparator variant was identified in ClinVar or the literature for position 577 of NTRK3. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue pathogenic variants at Pro577.
Sources
pm5_candidates
PM6 No de novo observation with confirmed maternity/paternity has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- No parental testing data.
PP1 No segregation data are available for this variant in affected families. Details ▾Hide ▴
Evidence considered
- No segregation studies identified.
Still missing
- No family studies or cosegregation data.
PP2 No evidence that NTRK3 has a low rate of benign missense variation or a high missense Z-score to support PP2 application. Details ▾Hide ▴
Evidence considered
- No gene-level missense constraint data available for NTRK3.
Still missing
- Missense constraint metrics not evaluated.
PP3 Multiple lines of computational evidence do not consistently support a deleterious effect. REVEL score is 0.541 (borderline, just above the 0.5 threshold), BayesDel score is -0.141 (benign), and SpliceAI delta score is 0.00 (no predicted splicing impact). The mixed in silico profile does not meet the requirement for multiple concordant pathogenic predictions. Details ▾Hide ▴
Evidence considered
- REVEL: 0.541 (borderline pathogenic)
- BayesDel: -0.141 (benign)
- SpliceAI: max delta = 0.00 (no splicing impact)
Sources
PP4 No patient phenotype data are available to assess specificity of presentation for an NTRK3-related disorder. Details ▾Hide ▴
Evidence considered
- No patient phenotype information available.
Still missing
- No clinical phenotype provided for the proband.
PP5 This variant is absent from ClinVar; no expert panel or reputable source has classified it as pathogenic. Details ▾Hide ▴
BA1 The variant is present at extremely low frequency in gnomAD (v2.1 AF = 7.97e-6), far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 7.97e-6 (0.0008%)
- well below 1%
- gnomAD v4.1 AF = 1.24e-6 (0.0001%)
Sources
BS1 The variant allele frequency in gnomAD (v2.1 AF = 7.97e-6) is far below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 7.97e-6 (0.0008%)
- well below 0.3%
- gnomAD v4.1 AF = 1.24e-6 (0.0001%)
Sources
BS2 No data are available demonstrating this variant in healthy adults with full penetrance expected. Details ▾Hide ▴
Evidence considered
- No healthy adult control data identified.
Still missing
- No control cohort data with phenotype annotation.
BS3 No functional studies demonstrating no deleterious effect of this variant are available. Details ▾Hide ▴
Evidence considered
- No functional assay data available for this variant.
Still missing
- No benign functional evidence.
BS4 No segregation data are available to demonstrate lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
- No segregation or family studies identified.
Still missing
- No cosegregation data.
BP1 There is no established evidence that NTRK3-related disease is caused exclusively by truncating variants; missense variants have not been excluded as a disease mechanism. Details ▾Hide ▴
Evidence considered
- NTRK3 disease mechanism not restricted to truncating variants.
BP2 No observation of this variant in trans with a known pathogenic variant has been reported. Details ▾Hide ▴
Evidence considered
- No in trans data available.
Still missing
- No phase data with pathogenic variants.
BP5 No alternate molecular basis for the observed phenotype has been identified in this case. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause identified.
Still missing
- No data on other variants or diagnoses in the proband.
BP6 This variant is absent from ClinVar; no reputable source has classified it as benign. Details ▾Hide ▴
PS5 No evidence for a novel disease mechanism associated with this variant is available. Details ▾Hide ▴
Evidence considered
- No novel disease mechanism data identified.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001012338.2:c.1730C>T is a missense variant (p.Pro577Leu); it does not fall into the null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus) required for PVS1 under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a predicted null variant.
Sources
BP7 N/AThis is a missense variant (c.1730C>T, p.Pro577Leu), not a synonymous variant; BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not synonymous.
Identifiers
- Gene
- NTRK3
- Transcript
- NM_001012338.2
- Coding (HGVS c.)
- NM_001012338.2:c.1730C>T
- Protein (HGVS p.)
- NP_001012338.1:p.(Pro577Leu)
- GRCh38
- chr15:87933171 G>A
- GRCh37
- chr15:88476402 G>A
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
2 / 1,614,122 alleles
AF 1.24e-06 · 0 homozygotes · FAF 5.53e-06
gnomAD v2.1
2 / 251,054 alleles
AF 7.97e-06 · 0 homozygotes · FAF 9.58e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,614,122 alleles · 0 hom · FAF 5.5e-06
| Admixed American2 / 60,016 | 3.3e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 8e-06 · 2 / 251,054 alleles · 0 hom · FAF 9.6e-06
| Admixed American2 / 34,578 | 5.8e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23906e-06; MAF= 0.00012%, 2/1614122 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33244e-05; MAF= 0.00333%, 2/60016 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96641e-06; MAF= 0.00080%, 2/251054 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.78402e-05; MAF= 0.00578%, 2/34578 alleles, homozygotes = 0); grpmax FAF= 9.58e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.541
- BayesDel
- -0.141
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact. BayesDel score is -0.141 (benign), SpliceAI predicts no splicing alteration (max delta = 0.00), and REVEL score is 0.541 (only borderline above the pathogenic threshold). The preponderance of in silico evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.141 (benign prediction)
- SpliceAI: max delta = 0.00 (no splicing impact)
- REVEL: 0.541 (borderline
- does not independently override benign signals)
Sources
PP3 Multiple lines of computational evidence do not consistently support a deleterious effect. REVEL score is 0.541 (borderline, just above the 0.5 threshold), BayesDel score is -0.141 (benign), and SpliceAI delta score is 0.00 (no predicted splicing impact). The mixed in silico profile does not meet the requirement for multiple concordant pathogenic predictions. Details ▾Hide ▴
Evidence considered
- REVEL: 0.541 (borderline pathogenic)
- BayesDel: -0.141 (benign)
- SpliceAI: max delta = 0.00 (no splicing impact)
Sources
BP7 N/AThis is a missense variant (c.1730C>T, p.Pro577Leu), not a synonymous variant; BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.541. BayesDel score = -0.140911.
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
2 / 1,614,122 recorded alleles
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_001012338.2%3Ac.1730C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/15-88476402-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr15-87933171-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/15-87933171-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001012338.2%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/NTRK3/P577L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NTRK3+c.1730C%3ET
- 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= 1.23906e-06; MAF= 0.00012%, 2/1614122 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33244e-05; MAF= 0.00333%, 2/60016 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96641e-06; MAF= 0.00080%, 2/251054 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.78402e-05; MAF= 0.00578%, 2/34578 alleles, homozygotes = 0); grpmax FAF= 9.58e-06.
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 = 0.541. BayesDel score = -0.140911.
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.