rs753168976

Variant names:

• chr6-24495046-C-A
• rs753168976
• NM_001080.3:c.50C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-24495046-C-A
• chr6-24495046-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001080.3(ALDH5A1):​c.50C>A​(p.Ser17*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000747 in 1,205,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S17S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 0 publications found

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]

GPLD1 (HGNC:4459): (glycosylphosphatidylinositol specific phospholipase D1) Many proteins are tethered to the extracellular face of eukaryotic plasma membranes by a glycosylphosphatidylinositol (GPI) anchor. The GPI-anchor is a glycolipid found on many blood cells. The protein encoded by this gene is a GPI degrading enzyme. Glycosylphosphatidylinositol specific phospholipase D1 hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans, thereby releasing the attached protein from the plasma membrane. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 142 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.50C>A	p.Ser17*	stop_gained	Exon 1 of 10	ENST00000357578.8	NP_001071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.50C>A	p.Ser17*	stop_gained	Exon 1 of 10	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000747 AC: 9 AN: 1205068 Hom.: 0 Cov.: 31 AF XY: 0.00000681 AC XY: 4 AN XY: 587232

African (AFR) AF: 0.00 AC: 0 AN: 25588

American (AMR) AF: 0.00 AC: 0 AN: 20642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18004

East Asian (EAS) AF: 0.00 AC: 0 AN: 29900

South Asian (SAS) AF: 0.0000472 AC: 2 AN: 42394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3316

European-Non Finnish (NFE) AF: 0.00000708 AC: 7 AN: 989232

Other (OTH) AF: 0.00 AC: 0 AN: 48432

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	30
DANN	Benign	0.87
Eigen	Benign	-0.55
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.013	N
PhyloP100		-1.2
Vest4		0.46
GERP RS		-5.8
PromoterAI		-0.0013	Neutral
Mutation Taster		=7/193	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs753168976; hg19: chr6-24495274;