NM_001012338.2:c.1795C>G (p.His599Asp) is a missense variant in NTRK3. It is absent from ClinVar and no publications describe this variant. Computational evidence (REVEL 0.937) supports a deleterious effect at supporting strength (PP3).1 PVS1 is not applicable as this is a missense variant. PM5 is not applicable as no same-residue pathogenic comparator exists. PM2, BA1, and BS1 could not be assessed due to gnomAD v2/v4 data unavailability (query timeout). No functional, segregation, case-control, or de novo data exist.2 With only PP3 at supporting strength and no other pathogenic criteria met, the variant does not reach even the lowest Likely Pathogenic threshold (1 Moderate + 4 Supporting or equivalent). It cannot be classified as Benign or Likely Benign either, as no benign criteria are met. The appropriate classification is Variant of Uncertain Significance (VUS).3
NTRK3
Final classification
VUS
NTRK3 c.1795C>G · p.His599Asp
NTRK3
NM_001012338.2:c.1795C>G (p.His599Asp) is a missense variant in NTRK3. It is absent from ClinVar and no publications describe this variant. Computational evidence (REVEL 0.937) supports a deleterious effect at supporting strength (PP3).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PP3 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PP3
VUS
NTRK3 c.1795C>G
PP3
→
VUS
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
✓
PP3
supporting
Pathogenic
REVEL score 0.937 predicts a deleterious effect on protein function. BayesDel additive score 0.387 is ambiguous (below the typical deleterious threshold). SpliceAI max delta score 0.00 indicates no predicted splicing impact. REVEL alone provides one line of computational evidence supporting pathogenicity; the conflicting/ambiguous BayesDel score precludes upgrading PP3 to moderate strength.
REVEL: 0.937 (deleterious prediction).BayesDel additive: 0.387 (ambiguous).SpliceAI max delta: 0.00 (no splice effect).
Assessed · not applied
Pathogenic
PS1
No alternative pathogenic missense variant at the same amino acid position (His599) has been reported.
PS2
No de novo occurrence data available for this variant.
PS3
No functional studies have been performed on this variant.
PS4
The variant is absent from ClinVar and no case-control or statistical association data are available.
PM1
The variant (p.His599Asp) resides in the NTRK3 tyrosine kinase domain (exon 16), but cancerhotspots.org does not identify this residue as a statistically significant mutational hotspot.
PM2
gnomAD v2.1 and v4.1 queries timed out during evidence gathering; population frequency data from the major reference databases is unavailable.
PM6
No de novo occurrence data available for this variant.
PP1
No co-segregation data available.
PP2
HCI prior score is unavailable for NTRK3 (gene not supported by the HCI prior database).
PP4
No phenotype or clinical data are available for the proband carrying this variant.
PP5
The variant is absent from ClinVar.
Benign
BA1
gnomAD v2.1 and v4.1 population frequency data are unavailable due to query timeout during evidence gathering.
BS1
gnomAD v2.1 and v4.1 population frequency data are unavailable due to query timeout.
BS2
No observation of this variant in a healthy adult control population has been reported.
BS3
No functional studies demonstrating a neutral or benign effect of this variant have been identified.
BS4
No segregation data demonstrating lack of co-segregation with disease are available.
BP1
BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease.
BP2
No observation of this variant in trans with a known pathogenic variant has been reported.
BP4
REVEL score 0.937 strongly predicts a deleterious effect, directly contradicting BP4.
BP5
No alternative molecular basis for disease has been identified in this case.
BP6
The variant is absent from ClinVar.
N/A · 3
PVS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v2.1
v4.1
This variant is absent from gnomAD v4.1.
v2.1
This variant is absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
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 = 0.937. BayesDel score = 0.387164.
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