rs578095133
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_002529.4(NTRK1):c.311G>A(p.Arg104His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. R104C) 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NTRK1 | NM_002529.4 | c.311G>A | p.Arg104His | missense_variant | 3/17 | ENST00000524377.7 | |
NTRK1 | NM_001012331.2 | c.311G>A | p.Arg104His | missense_variant | 3/16 | ||
NTRK1 | NM_001007792.1 | c.221G>A | p.Arg74His | missense_variant | 4/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NTRK1 | ENST00000524377.7 | c.311G>A | p.Arg104His | missense_variant | 3/17 | 1 | NM_002529.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251186Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135738
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461826Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 727210
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74330
ClinVar
Submissions by phenotype
Hereditary insensitivity to pain with anhidrosis Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 22, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 104 of the NTRK1 protein (p.Arg104His). This variant is present in population databases (rs578095133, gnomAD 0.01%). 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: 456617). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 17, 2024 | The c.311G>A (p.R104H) alteration is located in exon 3 (coding exon 3) of the NTRK1 gene. This alteration results from a G to A substitution at nucleotide position 311, causing the arginine (R) at amino acid position 104 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at