1-156868592-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_002529.4(NTRK1):c.662G>T(p.Gly221Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,551,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G221D) has been classified as Uncertain significance.
Frequency
Consequence
NM_002529.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NTRK1 | NM_002529.4 | c.662G>T | p.Gly221Val | missense_variant | Exon 6 of 17 | ENST00000524377.7 | NP_002520.2 | |
NTRK1 | NM_001012331.2 | c.662G>T | p.Gly221Val | missense_variant | Exon 6 of 16 | NP_001012331.1 | ||
NTRK1 | NM_001007792.1 | c.572G>T | p.Gly191Val | missense_variant | Exon 7 of 17 | NP_001007793.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000193 AC: 3AN: 155128Hom.: 0 AF XY: 0.0000122 AC XY: 1AN XY: 81978
GnomAD4 exome AF: 0.0000214 AC: 30AN: 1399418Hom.: 0 Cov.: 33 AF XY: 0.0000203 AC XY: 14AN XY: 690316
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74370
ClinVar
Submissions by phenotype
Hereditary insensitivity to pain with anhidrosis Uncertain:2
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 221 of the NTRK1 protein (p.Gly221Val). This variant is present in population databases (rs369478563, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with NTRK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 566941). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NTRK1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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Inborn genetic diseases Uncertain:1
The c.662G>T (p.G221V) alteration is located in exon 6 (coding exon 6) of the NTRK1 gene. This alteration results from a G to T substitution at nucleotide position 662, causing the glycine (G) at amino acid position 221 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at