rs149482918

chr6-24520416-G-Achr6-24520416-G-Cchr6-24520416-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080.3(ALDH5A1):c.886G>A(p.Ala296Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,614,018 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (62 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.74

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011575848).
• BP6: Variant 6-24520416-G-A is Benign according to our data. Variant chr6-24520416-G-A is described in ClinVar as [Benign]. Clinvar id is 235630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00204 (311/152220) while in subpopulation AMR AF= 0.0183 (280/15286). AF 95% confidence interval is 0.0166. There are 6 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. 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.886G>A	p.Ala296Thr	missense_variant	6/10	ENST00000357578.8
ALDH5A1	NM_170740.1	c.925G>A	p.Ala309Thr	missense_variant	7/11
ALDH5A1	NM_001368954.1	c.742G>A	p.Ala248Thr	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.886G>A	p.Ala296Thr	missense_variant	6/10	1	NM_001080.3	P1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152102 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00679 AC: 1707 AN: 251374 Hom.: 54 AF XY: 0.00493 AC XY: 670 AN XY: 135858

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0482

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00144 AC: 2105 AN: 1461798 Hom.: 62 Cov.: 33 AF XY: 0.00117 AC XY: 852 AN XY: 727196

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0441

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152220 Hom.: 6 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74410

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.00494

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00551 AC: 669

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2019	This variant is associated with the following publications: (PMID: 29453517) -

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.028	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.87
MVP		0.98
MPC		0.88
ClinPred		0.047	T
GERP RS		5.5
Varity_R		0.66
gMVP		0.80

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: rs149482918; hg19: chr6-24520644; COSMIC: COSV104421073; COSMIC: COSV104421073;