About NTRK3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK3 c.428C>T, p.(Ser143Leu)
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
This variant is present at extremely low frequency in population databases. In gnomAD v2.1, the allele frequency is 7.96×10⁻⁶ (2/251,180 alleles, 0 homozygotes) and in gnomAD v4.1, the allele frequency is 4.96×10⁻⁶ (8/1,613,870 alleles, 0 homozygotes). The grpmax filtering allele frequency is 2.93×10⁻⁶, well below the 0.1% PM2 threshold for non-VCEP adjudication. The variant is absent from gnomAD-Canada.
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
8 / 1,613,870 alleles
gnomAD v4.1: 8 / 1,613,870 alleles. Recorded AF 4.95703e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96242e-06; MAF= 0.00080%, 2/251180 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.7614e-05; MAF= 0.00176%, 2/113546 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
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.
27 criteria with recorded statuses: 1 met · 5 not met · 17 not assessed · 4 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.428C>T is a missense variant in NTRK3 resulting in a serine to leucine substitution at codon 143 (p.Ser143Leu).
This variant is present at extremely low frequency in gnomAD population databases (v2.1 AF=7.96×10⁻⁶, 2/251,180 alleles; v4.1 AF=4.96×10⁻⁶, 8/1,613,870 alleles; no homozygotes; grpmax FAF=2.93×10⁻⁶), meeting PM2 at supporting strength.
The variant is absent from ClinVar and has not been reported in the germline literature. It is also absent from COSMIC (somatic cancer database) and OncoKB assigns an Unknown Oncogenic Effect classification.
In silico predictors are equivocal: REVEL score is 0.491 (borderline, below the 0.5 damaging threshold), BayesDel is 0.215, and SpliceAI predicts no splicing impact (max delta 0.03). Neither PP3 nor BP4 is met.
No functional studies, segregation data, de novo observations, or case-control data are available for this variant. The residue Ser143 is not located in a known mutational hotspot.
No CSPEC or VCEP framework exists for NTRK3. Applying generic ACMG/AMP 2015 rules, the only applicable criterion is PM2 (supporting). This is insufficient to classify the variant as likely pathogenic or likely benign.
Overall, NM_001012338.2:c.428C>T is classified as a Variant of Uncertain Significance (VUS) based on a single supporting pathogenic criterion (PM2) and no applicable benign criteria.
No criteria match.
Met · 1
PM2 SupportingThis variant is present at extremely low frequency in population databases. In gnomAD v2.1, the allele frequency is 7.96×10⁻⁶ (2/251,180 alleles, 0 homozygotes) and in gnomAD v4.1, the allele frequency is 4.96×10⁻⁶ (8/1,613,870 alleles, 0 homozygotes). The grpmax filtering allele frequency is 2.93×10⁻⁶, well below the 0.1% PM2 threshold for non-VCEP adjudication. The variant is absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=7.96e-06
- AC=2
- AN=251
- 180
- hom=0
- grpmax FAF=2.93e-06
- gnomAD v4.1: AF=4.96e-06
- AC=8
- AN=1
- 613
- 870
- grpmax FAF=2.92e-06
- gnomAD-Canada: absent
- Best subpopulation (European non-Finnish) v2.1 AF=1.76e-05
Sources
Not met · 5 · evaluated, threshold not reached
PM1 This variant does not lie within a statistically significant mutational hotspot in NTRK3, and no evidence places residue Ser143 within a well-established critical functional domain for which missense variation is a known disease mechanism. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue Ser143 is not a statistically significant hotspot
- No domain-level functional evidence available for this residue
PP3 In silico predictors do not provide consistent evidence of a deleterious effect. REVEL score is 0.491 (below the 0.5 threshold for damaging), BayesDel score is 0.215 (below the typical pathogenic threshold), and SpliceAI predicts no significant splice impact (max delta = 0.03). These results are equivocal and do not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.491 (borderline
- below 0.5 damaging threshold)
- BayesDel: 0.214812 (below pathogenic threshold)
- SpliceAI: max delta 0.03 (no splice impact)
Sources
BA1 The variant has an allele frequency far below the 1% BA1 threshold. In gnomAD v2.1, AF = 7.96×10⁻⁶ (0.0008%) and in gnomAD v4.1, AF = 4.96×10⁻⁶ (0.0005%). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=7.96e-06 (0.0008%)
- gnomAD v4.1: AF=4.96e-06 (0.0005%)
- Both far below 1% BA1 threshold
Sources
BS1 The variant has an allele frequency below the 0.3% BS1 threshold (non-VCEP). In gnomAD v2.1, AF = 7.96×10⁻⁶ (0.0008%) and in gnomAD v4.1, AF = 4.96×10⁻⁶ (0.0005%). The frequency is too low to support a benign interpretation under BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=7.96e-06 (0.0008%
- well below 0.3%)
- gnomAD v4.1: AF=4.96e-06 (0.0005%
Sources
BP4 Multiple lines of computational evidence do not consistently suggest no impact on gene product. REVEL score (0.491) is borderline and not clearly benign. BayesDel (0.215) is below the pathogenic threshold but not strongly indicative of benign effect. SpliceAI shows no splice impact (max delta 0.03). Overall, the in silico evidence is equivocal and does not meet the threshold for BP4. Details ▾Hide ▴
Evidence considered
- REVEL: 0.491 (indeterminate)
- BayesDel: 0.214812 (not strongly benign)
- SpliceAI: max delta 0.03 (no splice impact)
Sources
Not assessed · 17 · no assessment recorded
PS1 No known pathogenic variant with the same amino acid change (Ser143Leu) via a different nucleotide substitution has been identified in ClinVar or the literature for NTRK3. Details ▾Hide ▴
Evidence considered
- ClinVar: no variant entries for NTRK3 c.428C>T or any variant at this residue
- PM5 candidate search: zero same-residue candidates found
Still missing
- No comparator pathogenic variant with same amino acid change exists
Sources
clinvar ↗pm5_candidates
PS2 No de novo occurrence data (with confirmed paternity and maternity) are available for this variant. Details ▾Hide ▴
Still missing
- No de novo data available in ClinVar or literature
PS3 No well-established in vitro or in vivo functional studies have been identified for NM_001012338.2:c.428C>T. OncoKB classifies this variant as Unknown Oncogenic Effect, and no variant-specific functional publications were found. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific supporting PMIDs
- Literature pass: 0 PMIDs found across evidence sources
Still missing
- No functional studies available for this variant
Sources
PS4 No case-control or cohort data comparing the prevalence of this variant in affected individuals versus controls are available. Details ▾Hide ▴
Still missing
- No case-control or cohort prevalence data available
PM6 No de novo occurrence data (without confirmation of paternity and maternity) are available for this variant. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 No cosegregation data are available for this variant in affected families. Details ▾Hide ▴
Still missing
- No segregation data available
PP2 Missense constraint data (e.g., missense Z-score, gnomAD o/e metric) are not available for NTRK3 in the evidence brief. HCI prior probability is not available for this gene. PP2 cannot be assessed without a gene-level metric of missense constraint. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported
- No missense constraint data available
Still missing
- Missense constraint metrics unavailable for NTRK3
PP4 No phenotype or family history data are available for individuals harboring this variant to assess whether the phenotype is highly specific for NTRK3-related disease. Details ▾Hide ▴
Still missing
- No phenotype data available for variant carriers
PP5 This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source. Details ▾Hide ▴
Evidence considered
- ClinVar: no entries for this variant
Still missing
- No ClinVar or expert panel classification available
Sources
BS2 No data are available on whether this variant has been observed in a healthy adult individual in cis with a known pathogenic variant in NTRK3. Details ▾Hide ▴
Still missing
- No cis-phase observation data available
BS3 No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of this variant are available. Details ▾Hide ▴
Still missing
- No functional studies showing no deleterious effect
BS4 No segregation data in affected families are available to assess lack of cosegregation with disease. Details ▾Hide ▴
Still missing
- No segregation data available
BP1 Although a gene-level literature review suggests possible NTRK3 loss-of-function mechanism in germline disease, the supporting evidence is derived from papers that mention NTRK3 tangentially (e.g., expression in cylindromas, somatic alterations in tumor panels, or gene panels not specific to NTRK3). A well-established NTRK3 germline disease with truncating variants as the primary mechanism has not been definitively demonstrated. BP1 cannot be reliably applied without a curated CSPEC framework. Details ▾Hide ▴
Evidence considered
- PVS1 gene context claims LoF mechanism supported
- but supporting papers lack direct NTRK3 germline disease evidence
- No CSPEC/VCEP framework available for NTRK3
Still missing
- No curated NTRK3 germline disease mechanism established
- Truncating variants not confirmed as primary disease mechanism
Sources
pvs1_gene_context
BP2 No data are available on whether this variant has been observed in trans with a known pathogenic dominant variant in NTRK3. Details ▾Hide ▴
Still missing
- No trans-phase observation data available
BP5 No data are available on whether this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
BP6 This variant is absent from ClinVar and has not been reported as benign by any reputable source. Details ▾Hide ▴
Evidence considered
- ClinVar: no entries for this variant
Still missing
- No ClinVar or expert panel classification available
Sources
PS5 No known pathogenic missense variant at the same residue (Ser143) in NTRK3 has been identified to support PS5 (different nucleotide change, same amino acid change not applicable; different amino acid change would fall under PM5, which was also not applicable). Details ▾Hide ▴
Evidence considered
- PM5 candidate search: zero same-residue comparator variants
Still missing
- No pathogenic comparator variant at Ser143
Sources
pm5_candidates
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution (c.428C>T, p.Ser143Leu) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Variant bucket: other (missense)
- apply_generic_pvs1_framework: false
- ClinGen SVI PVS1 recommendations restrict PVS1 to null variants
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/AUnable to confirm classic same-residue PM5 semantics. No pathogenic missense comparator variants at residue Ser143 in NTRK3 were identified in ClinVar or through automated candidate harvesting. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: zero same-residue candidates
- ClinVar: no variant entries at this residue
Sources
pm5_candidatesclinvar ↗
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (p.Ser143Leu). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- NTRK3
- Transcript
- NM_001012338.2
- Coding (HGVS c.)
- NM_001012338.2:c.428C>T
- Protein (HGVS p.)
- NP_001012338.1:p.(Ser143Leu)
- GRCh38
- chr15:88147371 G>A
- GRCh37
- chr15:88690602 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
8 / 1,613,870 alleles
AF 4.96e-06 · 0 homozygotes · FAF 2.92e-06
gnomAD v2.1
2 / 251,180 alleles
AF 7.96e-06 · 0 homozygotes · FAF 2.93e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5e-06 · 8 / 1,613,870 alleles · 0 hom · FAF 2.9e-06
| European (non-Finnish)8 / 1,179,804 | 6.8e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 8e-06 · 2 / 251,180 alleles · 0 hom · FAF 2.9e-06
| European (non-Finnish)2 / 113,546 | 1.8e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.95703e-06; MAF= 0.00050%, 8/1613870 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.78079e-06; MAF= 0.00068%, 8/1179804 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96242e-06; MAF= 0.00080%, 2/251180 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.7614e-05; MAF= 0.00176%, 2/113546 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.491
- BayesDel
- 0.215
How the predictions were used
PP3 In silico predictors do not provide consistent evidence of a deleterious effect. REVEL score is 0.491 (below the 0.5 threshold for damaging), BayesDel score is 0.215 (below the typical pathogenic threshold), and SpliceAI predicts no significant splice impact (max delta = 0.03). These results are equivocal and do not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.491 (borderline
- below 0.5 damaging threshold)
- BayesDel: 0.214812 (below pathogenic threshold)
- SpliceAI: max delta 0.03 (no splice impact)
Sources
BP4 Multiple lines of computational evidence do not consistently suggest no impact on gene product. REVEL score (0.491) is borderline and not clearly benign. BayesDel (0.215) is below the pathogenic threshold but not strongly indicative of benign effect. SpliceAI shows no splice impact (max delta 0.03). Overall, the in silico evidence is equivocal and does not meet the threshold for BP4. Details ▾Hide ▴
Evidence considered
- REVEL: 0.491 (indeterminate)
- BayesDel: 0.214812 (not strongly benign)
- SpliceAI: max delta 0.03 (no splice impact)
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (p.Ser143Leu). Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.491. BayesDel score = 0.214812.
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
8 / 1,613,870 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
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.428C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/15-88690602-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr15-88147371-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/15-88147371-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001012338.2%3Ac.4…
- OncoKB ↗www.oncokb.org/gene/NTRK3/S143L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NTRK3+c.428C%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= 4.95703e-06; MAF= 0.00050%, 8/1613870 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.78079e-06; MAF= 0.00068%, 8/1179804 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96242e-06; MAF= 0.00080%, 2/251180 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.7614e-05; MAF= 0.00176%, 2/113546 alleles, homozygotes = 0); grpmax FAF= 2.93e-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 = 0.03). REVEL score = 0.491. BayesDel score = 0.214812.
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.