rs1301821497
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001080.3(ALDH5A1):c.610-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001080.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALDH5A1 | NM_001080.3 | c.610-2A>G | splice_acceptor_variant, intron_variant | ENST00000357578.8 | NP_001071.1 | |||
ALDH5A1 | NM_170740.1 | c.610-2A>G | splice_acceptor_variant, intron_variant | NP_733936.1 | ||||
ALDH5A1 | NM_001368954.1 | c.610-2A>G | splice_acceptor_variant, intron_variant | NP_001355883.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152114Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251486Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461348Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 726990
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152114Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74302
ClinVar
Submissions by phenotype
Succinate-semialdehyde dehydrogenase deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 06, 2023 | Disruption of this splice site has been observed in individual(s) with succinate semialdehyde dehydrogenase deficiency (PMID: 14635103). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 3 of the ALDH5A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALDH5A1 are known to be pathogenic (PMID: 14635103). This variant is also known as IVS3-2G>A. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 459990). - |
Pathogenic, criteria provided, single submitter | curation | Elsea Laboratory, Baylor College of Medicine | Mar 08, 2021 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 01, 2023 | Reported previously in multiple unrelated patients with SSADH deficiency who also harbored a second ALDH5A1 variant; however phase was undetermined (Akaboshi et al., 2003; Niemi et al., 2014).; Published functional studies demonstrate the variant results in a frameshift with detrimental effect on the protein (Akaboshi et al., 2003).; Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25558043, 31, 25525159, 14635103, 27896081, 32395407, 31589614, 32887777, 31440721) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at