11-2164237-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000360.4(TH):c.1490G>A(p.Gly497Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G497S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000360.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TH | NM_000360.4 | c.1490G>A | p.Gly497Asp | missense_variant | Exon 13 of 13 | ENST00000352909.8 | NP_000351.2 | |
TH | NM_199292.3 | c.1583G>A | p.Gly528Asp | missense_variant | Exon 14 of 14 | NP_954986.2 | ||
TH | NM_199293.3 | c.1571G>A | p.Gly524Asp | missense_variant | Exon 14 of 14 | NP_954987.2 | ||
TH | XM_011520335.3 | c.1502G>A | p.Gly501Asp | missense_variant | Exon 13 of 13 | XP_011518637.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TH | ENST00000352909.8 | c.1490G>A | p.Gly497Asp | missense_variant | Exon 13 of 13 | 1 | NM_000360.4 | ENSP00000325951.4 | ||
TH | ENST00000381178.5 | c.1583G>A | p.Gly528Asp | missense_variant | Exon 14 of 14 | 1 | ENSP00000370571.1 | |||
TH | ENST00000381175.5 | c.1571G>A | p.Gly524Asp | missense_variant | Exon 14 of 14 | 1 | ENSP00000370567.1 | |||
TH | ENST00000333684.9 | c.1208G>A | p.Gly403Asp | missense_variant | Exon 11 of 11 | 1 | ENSP00000328814.6 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000618 AC: 9AN: 145726Hom.: 0 AF XY: 0.0000635 AC XY: 5AN XY: 78742
GnomAD4 exome AF: 0.00000688 AC: 9AN: 1308738Hom.: 0 Cov.: 31 AF XY: 0.00000782 AC XY: 5AN XY: 639056
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
Autosomal recessive DOPA responsive dystonia Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 528 of the TH protein (p.Gly528Asp). This variant is present in population databases (rs753632777, gnomAD 0.08%). 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: 936679). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at