rs118203983
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001080.3(ALDH5A1):c.1234C>T(p.Arg412Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000428 in 1,613,944 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000044 ( 0 hom. )
Consequence
ALDH5A1
NM_001080.3 stop_gained
NM_001080.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.64
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-24528057-C-T is Pathogenic according to our data. Variant chr6-24528057-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24528057-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH5A1 | NM_001080.3 | c.1234C>T | p.Arg412Ter | stop_gained | 8/10 | ENST00000357578.8 | |
ALDH5A1 | NM_170740.1 | c.1273C>T | p.Arg425Ter | stop_gained | 9/11 | ||
ALDH5A1 | NM_001368954.1 | c.1090C>T | p.Arg364Ter | stop_gained | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH5A1 | ENST00000357578.8 | c.1234C>T | p.Arg412Ter | stop_gained | 8/10 | 1 | NM_001080.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152106Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
5
AN:
152106
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251426Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135874
GnomAD3 exomes
AF:
AC:
8
AN:
251426
Hom.:
AF XY:
AC XY:
5
AN XY:
135874
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32AN XY: 727216
GnomAD4 exome
AF:
AC:
64
AN:
1461838
Hom.:
Cov.:
31
AF XY:
AC XY:
32
AN XY:
727216
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74306
GnomAD4 genome
?
AF:
AC:
5
AN:
152106
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74306
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
?
AF:
AC:
6
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Succinate-semialdehyde dehydrogenase deficiency Pathogenic:6
Pathogenic, criteria provided, single submitter | research | Cavalleri Lab, Royal College of Surgeons in Ireland | Dec 11, 2019 | ACMG evidence PVS1, PM3, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 07, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1358). This premature translational stop signal has been observed in individual(s) with succinic semialdehyde dehydrogenase deficiency (PMID: 11243727). This variant is present in population databases (rs118203983, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg412*) in the ALDH5A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDH5A1 are known to be pathogenic (PMID: 14635103). - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 30, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2003 | - - |
Pathogenic, criteria provided, single submitter | curation | Elsea Laboratory, Baylor College of Medicine | Mar 08, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 15, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28191889, 31589614, 25525159, 32238909, 32395407, 25558043, Hongliang2019[article], 16442322, 25431891, 20804942, 14635103, 11243727) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at