NM_002529.3:c.1031G>A

NTRK1 · NP_002520.2:p.(Gly344Glu) · NM_002529.3

GRCh37: chr1:156843605 G>A · GRCh38: chr1:156873813 G>A

Gene: NTRK1 Transcript: NM_002529.3

Final call

VUS

PM2 supporting

Variant details

Gene

NTRK1

Transcript

NM_002529.3

Protein

NP_002520.2:p.(Gly344Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002529.3:c.1031G>A (p.Gly344Glu) in NTRK1 is absent from all population databases (gnomAD v2.1, v4.1, Canada v1.0), meeting PM2 at supporting strength.

No additional pathogenic or benign criteria were met. The variant is absent from ClinVar, has no published functional data, and in silico predictors are discordant. COSMIC reports one somatic occurrence (COSV107439993).

Under generic ACMG/AMP 2015 rules, PM2_supporting alone is insufficient for classification. This 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	NM_002529.3:c.1031G>A is a missense variant (p.Gly344Glu) and does not fall into the null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus variants) required for PVS1 application under the ClinGen SVI PVS1 decision framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No different nucleotide substitution at codon 344 resulting in the same amino acid change (p.Gly344Glu) has been reported as pathogenic. The variant is absent from ClinVar entirely, and no alternative nucleotide change at this codon was identified in any source.	clinvar
PS2	Not met	No de novo observation has been reported for this variant; no parental or trio testing data are available in ClinVar, the literature, or any other evidence source.
PS3	Not met	No variant-specific functional studies were identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no curated functional evidence. No publications with experimental characterization of p.Gly344Glu were found.	oncokb
PS4	Not met	No case-control or prevalence data are available for this variant. It is absent from ClinVar with no submitted classifications, and no published patient cohorts mention c.1031G>A.	clinvar
PS5	Not met	No different pathogenic missense variant at codon 344 was identified. The PM5 candidate harvest returned zero candidates at this residue, and ClinVar contains no entries for any variant at this position.	clinvar pm5_candidates
PM1	Not met	Position Gly344 is not in a statistically significant mutational hotspot per cancerhotspots.org. No ClinGen CSPEC or VCEP framework identifies this residue as a critical functional domain. In the absence of domain-level hotspot characterization specific to this residue, PM1 cannot be applied.
PM2	Met	NM_002529.3:c.1031G>A is absent from all large population databases (gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0), with an allele frequency of 0.00, well below the 0.1% threshold for PM2 in the generic ACMG/AMP framework.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No different pathogenic missense change at codon 344 was identified. The PM5 candidate collection returned zero candidates at this residue, and ClinVar has no entries for any variant at position Gly344.	clinvar pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant. No trio sequencing or parental confirmation data are available in any evidence source.
PP1	Not met	No segregation data are available. No family studies or cosegregation analyses mentioning this variant were identified in ClinVar or the literature.
PP2	Not met	No HCI prior constraint data are available for NTRK1; the gene is not supported in the HCI prior database. Missense constraint cannot be assessed without gene-level benign missense rate data.
PP3	Not met	In silico predictors are discordant and do not provide multiple concordant lines of deleterious evidence. REVEL score is borderline at 0.525, BayesDel is benign at 0.160, and SpliceAI predicts no splice impact (max delta 0.00). A single borderline score does not satisfy PP3's requirement for multiple lines of computational evidence.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data are available for this case. The variant is absent from ClinVar and no published case reports describe a patient with this specific variant.
PP5	Not met	This variant is absent from ClinVar. No expert panel or reputable source has classified it as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD (AF = 0.00) and does not meet the >1% allele frequency threshold for BA1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD (AF = 0.00) and does not meet the >0.3% allele frequency threshold for BS1 in the generic ACMG/AMP framework.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No homozygous observations in healthy adults are reported. The variant is absent from all population databases, providing no data on homozygosity in unaffected individuals.
BS3	Not met	No well-established functional studies demonstrating no deleterious effect exist for this variant. OncoKB reports Unknown Oncogenic Effect, and no publications with functional characterization of p.Gly344Glu were identified.	oncokb
BS4	Not met	No segregation or non-segregation data are available. No family studies involving this variant were identified in any evidence source.
BP1	Not met	NTRK1-associated congenital insensitivity to pain with anhidrosis (CIPA) is caused by both missense and truncating loss-of-function variants. BP1 applies only when a gene's disease mechanism is exclusively through truncating variants, which is not the case for NTRK1.
BP2	Not met	No phase or trans/cis configuration data are available for this variant. No observation in trans with a known pathogenic variant has been reported.
BP4	Not met	While BayesDel (0.160) and SpliceAI (max delta 0.00) are consistent with a benign interpretation, the REVEL score of 0.525 is borderline pathogenic. This discordance means there are not multiple concordant lines of benign computational evidence required for BP4.	revel bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in this case. No data are available to suggest another causal variant explains the phenotype.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified it as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_002529.3:c.1031G>A is a missense variant (p.Gly344Glu), not a synonymous variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This is a single-nucleotide substitution.
PM3	N/A	PM3 requires observation in trans with a pathogenic variant for recessive disorders. No phase or trans configuration data are available for this variant.
PM4	N/A	PM4 applies to protein-length-altering variants (in-frame deletions/insertions, stop-loss). This is a single-nucleotide missense substitution.

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.