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.1 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.2 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.3 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).4
NTRK3
Final classification
VUS
NTRK3 c.1730C>T · p.Pro577Leu
NTRK3
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.
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.
Classification rationale
PM2
BP4
VUS
NTRK3 c.1730C>T
PM2 + BP4
→
VUS
2
bayesdelspliceai ↗revel
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 · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: AF = 7.97e-62/251054 alleles
✓
BP4
supporting
Benign
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: -0.141 (benign prediction)SpliceAI: max delta = 0.00 (no splicing impact)REVEL: 0.541 (borderline
Assessed · not applied
Pathogenic
PS1
No ClinVar entry exists for a pathogenic variant with the same amino acid change (p.Pro577Leu) at this position.
PS2
No de novo occurrence data are available for this variant in any curated source.
PS3
No variant-specific functional studies were identified.
PS4
No case-control or cohort data are available to support enrichment of this variant in affected individuals.
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.
PM5
No same-residue pathogenic comparator variant was identified in ClinVar or the literature for position 577 of NTRK3.
PM6
No de novo observation with confirmed maternity/paternity has been reported for this variant.
PP1
No segregation data are available for this variant in affected families.
PP2
No evidence that NTRK3 has a low rate of benign missense variation or a high missense Z-score to support PP2 application.
PP3
Multiple lines of computational evidence do not consistently support a deleterious effect.
PP4
No patient phenotype data are available to assess specificity of presentation for an NTRK3-related disorder.
PP5
This variant is absent from ClinVar; no expert panel or reputable source has classified it as pathogenic.
Benign
BA1
The variant is present at extremely low frequency in gnomAD (v2.1 AF = 7.97e-6), far below the 1% BA1 threshold.
BS1
The variant allele frequency in gnomAD (v2.1 AF = 7.97e-6) is far below the 0.3% BS1 threshold.
BS2
No data are available demonstrating this variant in healthy adults with full penetrance expected.
BS3
No functional studies demonstrating no deleterious effect of this variant are available.
BS4
No segregation data are available to demonstrate lack of cosegregation with disease.
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.
BP2
No observation of this variant in trans with a known pathogenic variant has been reported.
BP5
No alternate molecular basis for the observed phenotype has been identified in this case.
BP6
This variant is absent from ClinVar; no reputable source has classified it as benign.
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,614,122
0 hom · FAF 0.00055%
0 hom · FAF 0.00055%
Admixed American 2 / 60,016 |
0.0033% |
+ 9 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0008%
· 2 / 251,054
0 hom · FAF 0.00096%
0 hom · FAF 0.00096%
Admixed American 2 / 34,578 |
0.0058% |
+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-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 = 0.00). REVEL score = 0.541. BayesDel score = -0.140911.
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