rs58747567

chr6-24532164-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001080.3(ALDH5A1):c.1389T>C(p.Asp463=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00928 in 1,613,906 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (100 hom.)
• Consequence: ALDH5A1 NM_001080.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.74

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-24532164-T-C is Benign according to our data. Variant chr6-24532164-T-C is described in ClinVar as [Benign]. Clinvar id is 287826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24532164-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.74 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00681 (1037/152322) while in subpopulation NFE AF= 0.0117 (796/68018). AF 95% confidence interval is 0.011. There are 6 homozygotes in gnomad4. There are 468 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH5A1	NM_001080.3	c.1389T>C	p.Asp463=	synonymous_variant	9/10	ENST00000357578.8
ALDH5A1	NM_170740.1	c.1428T>C	p.Asp476=	synonymous_variant	10/11
ALDH5A1	NM_001368954.1	c.1245T>C	p.Asp415=	synonymous_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.1389T>C	p.Asp463=	synonymous_variant	9/10	1	NM_001080.3	P1

Frequencies

GnomAD3 genomes AF: 0.00681 AC: 1037 AN: 152204 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00616 AC: 1549 AN: 251444 Hom.: 18 AF XY: 0.00623 AC XY: 846 AN XY: 135894

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00954 AC: 13938 AN: 1461584 Hom.: 100 Cov.: 30 AF XY: 0.00932 AC XY: 6774 AN XY: 727112

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00423

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00805

GnomAD4 genome AF: 0.00681 AC: 1037 AN: 152322 Hom.: 6 Cov.: 33 AF XY: 0.00628 AC XY: 468 AN XY: 74488

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.0117

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00908 Hom.: 4

Bravo AF: 0.00732

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0108

EpiControl AF: 0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ALDH5A1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2019	- -

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 03, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.086
Dann	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs58747567; hg19: chr6-24532392; COSMIC: COSV62373265;