NM_002529.3:c.2004T>A

NTRK1 · NP_002520.2:p.(Asp668Glu) · NM_002529.3

GRCh37: chr1:156849112 T>A · GRCh38: chr1:156879320 T>A

Gene: NTRK1 Transcript: NM_002529.3

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

NTRK1

Transcript

NM_002529.3

Protein

NP_002520.2:p.(Asp668Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

REVEL meta-predictor score of 0.83 supports a deleterious effect, meeting PP3 at supporting strength.

No ClinVar entries exist for this variant; no functional data, no de novo reports, no case-control data, and no segregation data are available.

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).

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	PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus). This is a missense variant (c.2004T>A, p.Asp668Glu) and does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	PS1 requires a different pathogenic amino acid change at the same codon. No ClinVar entries exist for codon 668 of NTRK1; no pathogenic comparator variant at this residue has been identified.	clinvar
PS2	Not met	PS2 requires a confirmed de novo occurrence with both maternity and paternity confirmed. No de novo data are available for this variant.
PS3	Not met	PS3 requires well-established functional studies showing a damaging effect. No variant-specific functional data exist for c.2004T>A (p.Asp668Glu). OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No publications were identified that tested this variant or a systematically characterized range that includes position 668.	oncokb
PS4	Not met	PS4 requires a statistically significant enrichment of the variant in affected individuals compared to controls. No case-control data or prevalence data are available for this variant.
PS5	Not met	PS5 requires a different pathogenic nucleotide change at the same genomic position. No ClinVar entries exist for this nucleotide position (1-156849112-T-A or 1-156879320-T-A), and no PM5 candidates were identified at codon 668.	clinvar
PM1	Not met	PM1 requires location in a mutational hotspot or critical functional domain without benign variation. While p.Asp668Glu lies within the tyrosine kinase domain of NTRK1 (a critical functional domain), residue-specific hotspot analysis (cancerhotspots.org) was negative, and population-level constraint data for this domain are not available under the generic ACMG framework without CSPEC/VCEP guidance. Domain-level PM1 application cannot be confirmed.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	PM5 requires a different pathogenic missense change at the same amino acid residue. No ClinVar entries and no PM5 candidates were identified at codon 668 (p.Asp668). The PM5 candidate search found zero same-residue comparator variants.	clinvar pm5_candidates
PM6	Not met	PM6 requires a de novo observation without confirmation of maternity and paternity. No de novo data are available for this variant.
PP1	Not met	PP1 requires cosegregation with disease in multiple affected family members. No cosegregation data are available for this variant.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. While NTRK1 missense variants are a recognized mechanism in CIPA, population-level constraint metrics (e.g., missense Z-score) are not available in the evidence brief, so the 'low rate of benign missense variation' criterion cannot be confirmed under the generic ACMG framework.
PP3	Met	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 bayesdel spliceai
PP4	Not met	PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No patient phenotype or clinical data have been provided for this case.
PP5	Not met	PP5 requires a reputable source to have classified this variant as pathogenic. The variant is absent from ClinVar; no expert panel or clinical laboratory classification exists.	clinvar
BA1	Not met	BA1 requires an allele frequency >5% in population databases. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires an allele frequency greater than expected for the disorder (>0.3% under generic ACMG). The variant is absent from all population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. No data show this variant in healthy individuals.
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. No functional data are available for this variant.	oncokb
BS4	Not met	BS4 requires lack of segregation with disease in affected family members. No segregation data are available for this variant.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NTRK1-related CIPA is caused by both missense and truncating variants; missense variants are a recognized disease mechanism. BP1 does not apply.	pvs1_gene_context
BP2	Not met	BP2 requires observation in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant. No phase data are available for this variant.
BP4	Not met	BP4 requires multiple lines of computational evidence to suggest no impact on gene or gene product. REVEL score of 0.83 predicts a damaging effect, contradicting BP4. SpliceAI predicts no splicing impact but this alone is insufficient when a major meta-predictor supports pathogenicity.	revel bayesdel spliceai
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No data on alternate molecular diagnoses are available.
BP6	Not met	BP6 requires a reputable source to have classified this variant as benign. The variant is absent from ClinVar; no classification exists.	clinvar
BP7	N/A	BP7 is reserved for synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.2004T>A, p.Asp668Glu).

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.