NM_001012338.2:c.1730C>T

NTRK3 · NP_001012338.1:p.(Pro577Leu) · NM_001012338.2

GRCh37: chr15:88476402 G>A · GRCh38: chr15:87933171 G>A

Gene: NTRK3 Transcript: NM_001012338.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

NTRK3

Transcript

NM_001012338.2

Protein

NP_001012338.1:p.(Pro577Leu)

gnomAD AF

1.2390637138952322e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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	NM_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).	pvs1_generic_framework
PS1	Not met	No ClinVar entry exists for a pathogenic variant with the same amino acid change (p.Pro577Leu) at this position.	clinvar
PS2	Not met	No de novo occurrence data are available for this variant in any curated source.
PS3	Not met	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.	oncokb
PS4	Not met	No case-control or cohort data are available to support enrichment of this variant in affected individuals.
PS5	Not met	No evidence for a novel disease mechanism associated with this variant is available.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Not met	No same-residue pathogenic comparator variant was identified in ClinVar or the literature for position 577 of NTRK3.	pm5_candidates
PM6	Not met	No de novo observation with confirmed maternity/paternity has been reported for this variant.
PP1	Not met	No segregation data are available for this variant in affected families.
PP2	Not met	No evidence that NTRK3 has a low rate of benign missense variation or a high missense Z-score to support PP2 application.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data are available to assess specificity of presentation for an NTRK3-related disorder.
PP5	Not met	This variant is absent from ClinVar; no expert panel or reputable source has classified it as pathogenic.	clinvar
BA1	Not met	The variant is present at extremely low frequency in gnomAD (v2.1 AF = 7.97e-6), far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency in gnomAD (v2.1 AF = 7.97e-6) is far below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available demonstrating this variant in healthy adults with full penetrance expected.
BS3	Not met	No functional studies demonstrating no deleterious effect of this variant are available.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease.
BP1	Not met	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.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant has been reported.
BP4	Met	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.	bayesdel spliceai revel
BP5	Not met	No alternate molecular basis for the observed phenotype has been identified in this case.
BP6	Not met	This variant is absent from ClinVar; no reputable source has classified it as benign.	clinvar
BP7	N/A	This is a missense variant (c.1730C>T, p.Pro577Leu), not a synonymous variant; BP7 applies only to synonymous variants without predicted splice impact.

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