rs578023593
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_001080.3(ALDH5A1):c.1529C>T(p.Ser510Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,118 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S510S) has been classified as Likely benign.
Frequency
Consequence
NM_001080.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH5A1 | NM_001080.3 | c.1529C>T | p.Ser510Phe | missense_variant | 10/10 | ENST00000357578.8 | |
ALDH5A1 | NM_170740.1 | c.1568C>T | p.Ser523Phe | missense_variant | 11/11 | ||
ALDH5A1 | NM_001368954.1 | c.1385C>T | p.Ser462Phe | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH5A1 | ENST00000357578.8 | c.1529C>T | p.Ser510Phe | missense_variant | 10/10 | 1 | NM_001080.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152000Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251494Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135922
GnomAD4 exome Cov.: 31
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74336
ClinVar
Submissions by phenotype
Succinate-semialdehyde dehydrogenase deficiency Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | curation | Elsea Laboratory, Baylor College of Medicine | Mar 08, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 12, 2017 | This sequence change replaces serine with phenylalanine at codon 510 of the ALDH5A1 protein (p.Ser510Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs578023593, ExAC 0.01%). This variant has been reported in several individuals affected with succinic semialdehyde dehydrogenase deficiency (PMID: 26220405). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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