NM_001012338.2:c.1795C>G

NTRK3 · NP_001012338.1:p.(His599Asp) · NM_001012338.2

GRCh37: chr15:88476337 G>C · GRCh38: chr15:87933106 G>C

Gene: NTRK3 Transcript: NM_001012338.2

Final call

VUS

PP3 supporting

Variant details

Gene

NTRK3

Transcript

NM_001012338.2

Protein

NP_001012338.1:p.(His599Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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.

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).

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 is a missense variant (p.His599Asp). It does not fall into any of the generic PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is not applicable to missense variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternative pathogenic missense variant at the same amino acid position (His599) has been reported. The variant is absent from ClinVar and no literature describes a different pathogenic missense change at this residue.	clinvar
PS2	Not met	No de novo occurrence data available for this variant. No publications report a confirmed de novo observation of NM_001012338.2:c.1795C>G.
PS3	Not met	No functional studies have been performed on this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications with functional data for p.His599Asp were identified.	oncokb
PS4	Not met	The variant is absent from ClinVar and no case-control or statistical association data are available. Prevalence of this variant in affected individuals versus controls cannot be assessed.	clinvar
PS5	Not met	No statistically significant association data available. PS5 requires a validated association study demonstrating enrichment of the variant in affected individuals.
PM1	Not met	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. No published evidence demonstrates that missense variants in this specific region of NTRK3 are enriched in germline disease. The tyrosine kinase domain alone, in the absence of hotspot or domain-specific pathogenic enrichment data, is insufficient to meet PM1.
PM2	Not assessed	gnomAD v2.1 and v4.1 queries timed out during evidence gathering; population frequency data from the major reference databases is unavailable. Absent from gnomAD-Canada v1.0, but this population-specific database alone is insufficient to establish PM2 (<0.1% allele frequency threshold). Reliable assessment of PM2 requires gnomAD v2/v4 population-wide allele frequency data.	gnomad_canada
PM5	N/A	No pathogenic missense variant at the same amino acid residue (His599) has been reported in ClinVar. Per pm5_candidates.json, no same-residue comparator candidates were found. The automatic candidate harvesting confirmed no eligible comparators.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence data available for this variant. No publications report a confirmed de novo observation of NM_001012338.2:c.1795C>G.
PP1	Not met	No co-segregation data available. No family studies have been reported for this variant.
PP2	Not met	HCI prior score is unavailable for NTRK3 (gene not supported by the HCI prior database). Without this metric, the rate of benign missense variation in NTRK3 cannot be reliably estimated. Insufficient data to establish PP2.
PP3	Met	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 bayesdel spliceai
PP4	Not met	No phenotype or clinical data are available for the proband carrying this variant. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	The variant is absent from ClinVar. No reputable source — including expert panels or clinical testing laboratories — has classified this variant as pathogenic. PP5 requires a reputable source to have reported the variant as pathogenic.	clinvar
BA1	Not assessed	gnomAD v2.1 and v4.1 population frequency data are unavailable due to query timeout during evidence gathering. BA1 requires allele frequency >1% in population databases. Without the major reference population data, this criterion cannot be assessed.
BS1	Not assessed	gnomAD v2.1 and v4.1 population frequency data are unavailable due to query timeout. BS1 requires allele frequency >0.3% in population databases. Absent from gnomAD-Canada v1.0 (AC=0) but this limited population database is insufficient to independently satisfy BS1. Full assessment requires gnomAD v2/v4 data.	gnomad_canada
BS2	Not met	No observation of this variant in a healthy adult control population has been reported. No homozygous or heterozygous observations in unaffected individuals are documented in available databases.
BS3	Not met	No functional studies demonstrating a neutral or benign effect of this variant have been identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No publications report experimental characterization of p.His599Asp.	oncokb
BS4	Not met	No segregation data demonstrating lack of co-segregation with disease are available. No family studies have been reported for this variant.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. While NTRK3 loss-of-function is supported as a germline disease mechanism, there is insufficient evidence that NTRK3-related disease is caused primarily by truncating variants to the exclusion of missense variants. Missense variants in receptor tyrosine kinases (including the NTRK family) are well-established as a disease mechanism.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant has been reported. Furthermore, NTRK3-related germline disease has not been established as having a recessive inheritance pattern.
BP4	Not met	REVEL score 0.937 strongly predicts a deleterious effect, directly contradicting BP4. BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. The high REVEL score indicates a predicted damaging effect, not a benign one.	revel bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in this case. BP5 requires that an alternate molecular cause of disease has been found in the proband.
BP6	Not met	The variant is absent from ClinVar. No reputable source — including expert panels or clinical testing laboratories — has classified this variant as benign. BP6 requires a reputable source to have reported the variant as benign.	clinvar
BP7	N/A	BP7 is applicable only to synonymous (silent) variants with no predicted splicing impact. NM_001012338.2:c.1795C>G is a missense variant (p.His599Asp) producing an amino acid substitution — it is not synonymous. BP7 is therefore not applicable.

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.