rs2760138

Positions:

• chr6-24512609-G-A
• chr6-24512609-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001080.3(ALDH5A1):​c.727-2558G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.89 in 152,272 control chromosomes in the GnomAD database, including 61,098 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.89 (61098 hom., cov: 33)
• Consequence: ALDH5A1 NM_001080.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.727-2558G>A		intron_variant		ENST00000357578.8	NP_001071.1
ALDH5A1	NM_001368954.1	c.726+7624G>A		intron_variant			NP_001355883.1
ALDH5A1	NM_170740.1	c.765+741G>A		intron_variant			NP_733936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.727-2558G>A		intron_variant		1	NM_001080.3	ENSP00000350191	P1

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135407 AN: 152154 Hom.: 61059 Cov.: 33

Gnomad AFR AF: 0.957

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.740

Gnomad ASJ AF: 0.934

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.877

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.918

Gnomad OTH AF: 0.895

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.890 AC: 135497 AN: 152272 Hom.: 61098 Cov.: 33 AF XY: 0.881 AC XY: 65571 AN XY: 74446

Gnomad4 AFR AF: 0.957

Gnomad4 AMR AF: 0.739

Gnomad4 ASJ AF: 0.934

Gnomad4 EAS AF: 0.534

Gnomad4 SAS AF: 0.791

Gnomad4 FIN AF: 0.877

Gnomad4 NFE AF: 0.918

Gnomad4 OTH AF: 0.893

Alfa AF: 0.901 Hom.: 19102

Bravo AF: 0.884

Asia WGS AF: 0.706 AC: 2459 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.0
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs2760138; hg19: chr6-24512837;