rs374232934
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_001080.3(ALDH5A1):c.1480G>A(p.Glu494Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
ALDH5A1
NM_001080.3 missense
NM_001080.3 missense
Scores
8
4
7
Clinical Significance
Conservation
PhyloP100: 9.29
Genes affected
ALDH5A1 (HGNC:408): (aldehyde dehydrogenase 5 family member A1) This protein belongs to the aldehyde dehydrogenase family of proteins. This gene encodes a mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase. A deficiency of this enzyme, known as 4-hydroxybutyricaciduria, is a rare inborn error in the metabolism of the neurotransmitter 4-aminobutyric acid (GABA). In response to the defect, physiologic fluids from patients accumulate GHB, a compound with numerous neuromodulatory properties. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001080.3
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH5A1 | NM_001080.3 | c.1480G>A | p.Glu494Lys | missense_variant | 10/10 | ENST00000357578.8 | |
ALDH5A1 | NM_170740.1 | c.1519G>A | p.Glu507Lys | missense_variant | 11/11 | ||
ALDH5A1 | NM_001368954.1 | c.1336G>A | p.Glu446Lys | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH5A1 | ENST00000357578.8 | c.1480G>A | p.Glu494Lys | missense_variant | 10/10 | 1 | NM_001080.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000795 AC: 20AN: 251490Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135918
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GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727246
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74328
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Succinate-semialdehyde dehydrogenase deficiency Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 26, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 494 of the ALDH5A1 protein (p.Glu494Lys). This variant is present in population databases (rs374232934, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of ALDH5A1-related conditions (PMID: 28191889). ClinVar contains an entry for this variant (Variation ID: 529480). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 20, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory of Metabolic Disorders, Peking University First Hospital | Jun 24, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;D;N
REVEL
Pathogenic
Sift
Benign
D;D;D
Sift4G
Benign
T;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
0.90
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at