NM_001012338.2:c.428C>T

NTRK3 · NP_001012338.1:p.(Ser143Leu) · NM_001012338.2

GRCh37: chr15:88690602 G>A · GRCh38: chr15:88147371 G>A

Gene: NTRK3 Transcript: NM_001012338.2

Final call

VUS

PM2 supporting

Variant details

Gene

NTRK3

Transcript

NM_001012338.2

Protein

NP_001012338.1:p.(Ser143Leu)

gnomAD AF

4.957028756963076e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	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.	clinvar pm5_candidates
PS2	Not assessed	No de novo occurrence data (with confirmed paternity and maternity) are available for this variant.
PS3	Not assessed	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.	oncokb
PS4	Not assessed	No case-control or cohort data comparing the prevalence of this variant in affected individuals versus controls are available.
PS5	Not assessed	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).	pm5_candidates
PM1	Not met	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.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	Unable 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.	pm5_candidates clinvar
PM6	Not assessed	No de novo occurrence data (without confirmation of paternity and maternity) are available for this variant.
PP1	Not assessed	No cosegregation data are available for this variant in affected families.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	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	Not assessed	This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source.	clinvar
BA1	Not met	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%).	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	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	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of this variant are available.
BS4	Not assessed	No segregation data in affected families are available to assess lack of cosegregation with disease.
BP1	Not assessed	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.	pvs1_gene_context
BP2	Not assessed	No data are available on whether this variant has been observed in trans with a known pathogenic dominant variant in NTRK3.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	No data are available on whether this variant has been observed in a case with an alternate molecular basis for disease.
BP6	Not assessed	This variant is absent from ClinVar and has not been reported as benign by any reputable source.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (p.Ser143Leu).

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.