The variant NM_002529.3:c.2004T>A (p.Asp668Glu) in NTRK1 is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting PM2 at supporting strength.1 REVEL meta-predictor score of 0.83 supports a deleterious effect, meeting PP3 at supporting strength.2 No ClinVar entries exist for this variant; no functional data, no de novo reports, no case-control data, and no segregation data are available.3 Overall criteria met: PM2 (supporting), PP3 (supporting). Under generic ACMG/AMP 2015 classification rules, two supporting criteria do not reach the threshold for likely pathogenic (requires at least 1 moderate + 4 supporting, or 2 moderate + 2 supporting, or stronger combinations). The variant is classified as a variant of uncertain significance (VUS).4
NTRK1
Final classification
VUS
NTRK1 c.2004T>A · p.Asp668Glu
NTRK1
The variant NM_002529.3:c.2004T>A (p.Asp668Glu) in NTRK1 is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting PM2 at supporting strength.
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, PP3 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
NTRK1 c.2004T>A
PM2 + PP3
→
VUS
2
revel
4
generic_acmg_combination_rules
Gene diagram
· NM_002529.3 · variants mapped to exon structure
NTRK1
NM_002529.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
PM2 applies when a variant is absent from (or present at extremely low frequency in) population databases. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the generic ACMG threshold of <0.1% allele frequency.
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes + genomes).Absent from gnomAD-Canada v1.0 (HostSeq genomes).
✓
PP3
supporting
Pathogenic
PP3 applies when multiple lines of computational evidence support a deleterious effect. The REVEL meta-predictor score of 0.83 (range 0-1) exceeds the commonly used threshold of 0.5 and the more stringent 0.75 threshold, supporting a damaging prediction. BayesDel score is 0.459 (below the 0.5 threshold) and SpliceAI predicts no splicing impact (max delta 0.01). REVEL is a verified meta-predictor incorporating multiple constituent methods; its strong prediction supports PP3 at supporting level despite mixed signals from other predictors.
REVEL score: 0.83 (deleterious predictionverified meta-predictorPMID:36413997).
Assessed · not applied
Pathogenic
PS1
PS1 requires a different pathogenic amino acid change at the same codon.
PS2
PS2 requires a confirmed de novo occurrence with both maternity and paternity confirmed.
PS3
PS3 requires well-established functional studies showing a damaging effect.
PS4
PS4 requires a statistically significant enrichment of the variant in affected individuals compared to controls.
PM1
PM1 requires location in a mutational hotspot or critical functional domain without benign variation.
PM5
PM5 requires a different pathogenic missense change at the same amino acid residue.
PM6
PM6 requires a de novo observation without confirmation of maternity and paternity.
PP1
PP1 requires cosegregation with disease in multiple affected family members.
PP2
PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP4
PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5
PP5 requires a reputable source to have classified this variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >5% in population databases.
BS1
BS1 requires an allele frequency greater than expected for the disorder (>0.3% under generic ACMG).
BS2
BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age.
BS3
BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect.
BS4
BS4 requires lack of segregation with disease in affected family members.
BP1
BP1 applies to missense variants in genes where primarily truncating variants cause disease.
BP2
BP2 requires observation in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant.
BP4
BP4 requires multiple lines of computational evidence to suggest no impact on gene or gene product.
BP5
BP5 requires the variant to be found in a case with an alternate molecular basis for disease.
BP6
BP6 requires a reputable source to have classified this variant as benign.
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 = 0.01). REVEL score = 0.83. BayesDel score = 0.459299.
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. NTRK1, a receptor tyrosine kinase, is altered by gene fusions 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