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.1 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.2 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.3 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.4 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.
NTRK3
Final classification
VUS
NTRK3 c.428C>T · p.Ser143Leu
NTRK3
NM_001012338.2:c.428C>T is a missense variant in NTRK3 resulting in a serine to leucine substitution at codon 143 (p.Ser143Leu).
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.
Classification rationale
PM2
VUS
NTRK3 c.428C>T
PM2
→
VUS
3
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_001012338.2 · variants mapped to exon structure
NTRK3
NM_001012338.2
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v2.1: AF=7.96e-06AC=2AN=251
Assessed · not applied
Pathogenic
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.
PS2
No de novo occurrence data (with confirmed paternity and maternity) are available for this variant.
PS3
No well-established in vitro or in vivo functional studies have been identified for NM_001012338.2:c.428C>T.
PS4
No case-control or cohort data comparing the prevalence of this variant in affected individuals versus controls are available.
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.
PM6
No de novo occurrence data (without confirmation of paternity and maternity) are available for this variant.
PP1
No cosegregation data are available for this variant in affected families.
PP2
Missense constraint data (e.g., missense Z-score, gnomAD o/e metric) are not available for NTRK3 in the evidence brief.
PP3
In silico predictors do not provide consistent evidence of a deleterious effect.
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.
PP5
This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source.
Benign
BA1
The variant has an allele frequency far below the 1% BA1 threshold.
BS1
The variant has an allele frequency below the 0.3% BS1 threshold (non-VCEP).
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.
BS3
No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of this variant are available.
BS4
No segregation data in affected families are available to assess lack of cosegregation with disease.
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).
BP2
No data are available on whether this variant has been observed in trans with a known pathogenic dominant variant in NTRK3.
BP4
Multiple lines of computational evidence do not consistently suggest no impact on gene product.
BP5
No data are available on whether this variant has been observed in a case with an alternate molecular basis for disease.
BP6
This variant is absent from ClinVar and has not been reported as benign by any reputable source.
N/A · 4
PVS1 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0005%
· 8 / 1,613,870
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
European (non-Finnish) 8 / 1,179,804 |
0.00068% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008%
· 2 / 251,180
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
European (non-Finnish) 2 / 113,546 |
0.0018% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links