rs756331878
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The ENST00000381178.5(TH):c.149C>T(p.Ala50Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,603,852 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 (★★).
Frequency
Consequence
ENST00000381178.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TH | NM_000360.4 | c.91-853C>T | intron_variant | ENST00000352909.8 | |||
TH | NM_199292.3 | c.149C>T | p.Ala50Val | missense_variant | 2/14 | ||
TH | NM_199293.3 | c.137C>T | p.Ala46Val | missense_variant | 2/14 | ||
TH | XM_011520335.3 | c.103-853C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TH | ENST00000352909.8 | c.91-853C>T | intron_variant | 1 | NM_000360.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000661 AC: 1AN: 151262Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000175 AC: 4AN: 228868Hom.: 0 AF XY: 0.00000802 AC XY: 1AN XY: 124724
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1452590Hom.: 0 Cov.: 33 AF XY: 0.00000970 AC XY: 7AN XY: 721662
GnomAD4 genome ? AF: 0.00000661 AC: 1AN: 151262Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 73798
ClinVar
Submissions by phenotype
Autosomal recessive DOPA responsive dystonia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 50 of the TH protein (p.Ala50Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TH-related conditions. ClinVar contains an entry for this variant (Variation ID: 455992). 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 TH 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, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at