rs770884090
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_001080.3(ALDH5A1):c.676G>A(p.Val226Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,108 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. V226L) has been classified as Uncertain significance.
Frequency
Consequence
NM_001080.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH5A1 | NM_001080.3 | c.676G>A | p.Val226Met | missense_variant | 4/10 | ENST00000357578.8 | |
ALDH5A1 | NM_170740.1 | c.676G>A | p.Val226Met | missense_variant | 4/11 | ||
ALDH5A1 | NM_001368954.1 | c.676G>A | p.Val226Met | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH5A1 | ENST00000357578.8 | c.676G>A | p.Val226Met | missense_variant | 4/10 | 1 | NM_001080.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251462Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135910
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727242
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74368
ClinVar
Submissions by phenotype
Succinate-semialdehyde dehydrogenase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 226 of the ALDH5A1 protein (p.Val226Met). This variant is present in population databases (rs770884090, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ALDH5A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 571266). 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 expected to disrupt ALDH5A1 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at