11-2167882-C-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000360.4(TH):c.628G>T(p.Ala210Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A210T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000360.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TH | NM_000360.4 | c.628G>T | p.Ala210Ser | missense_variant | 5/13 | ENST00000352909.8 | |
TH | NM_199292.3 | c.721G>T | p.Ala241Ser | missense_variant | 6/14 | ||
TH | NM_199293.3 | c.709G>T | p.Ala237Ser | missense_variant | 6/14 | ||
TH | XM_011520335.3 | c.640G>T | p.Ala214Ser | missense_variant | 5/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TH | ENST00000352909.8 | c.628G>T | p.Ala210Ser | missense_variant | 5/13 | 1 | NM_000360.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455900Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 723748
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2023 | The c.721G>T (p.A241S) alteration is located in exon 6 (coding exon 6) of the TH gene. This alteration results from a G to T substitution at nucleotide position 721, causing the alanine (A) at amino acid position 241 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Autosomal recessive DOPA responsive dystonia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 18, 2022 | 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. 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 disruptive. This variant has not been reported in the literature in individuals affected with TH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 241 of the TH protein (p.Ala241Ser). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at