rs115784602

chr6-24520491-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001080.3(ALDH5A1):c.961G>A(p.Val321Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 1,614,160 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (20 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 3.03

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01294896).
• BP6: Variant 6-24520491-G-A is Benign according to our data. Variant chr6-24520491-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284072.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=1}. Variant chr6-24520491-G-A is described in Lovd as [Likely_benign]. Variant chr6-24520491-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00339 (516/152284) while in subpopulation NFE AF= 0.00575 (391/68028). AF 95% confidence interval is 0.00528. There are 3 homozygotes in gnomad4. There are 249 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH5A1	NM_001080.3	c.961G>A	p.Val321Met	missense_variant	6/10	ENST00000357578.8
ALDH5A1	NM_170740.1	c.1000G>A	p.Val334Met	missense_variant	7/11
ALDH5A1	NM_001368954.1	c.817G>A	p.Val273Met	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.961G>A	p.Val321Met	missense_variant	6/10	1	NM_001080.3	P1

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152166 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00331 AC: 833 AN: 251464 Hom.: 4 AF XY: 0.00312 AC XY: 424 AN XY: 135902

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00482

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00480 AC: 7017 AN: 1461876 Hom.: 20 Cov.: 33 AF XY: 0.00468 AC XY: 3406 AN XY: 727232

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00746

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.00387

Gnomad4 NFE exome AF: 0.00562

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152284 Hom.: 3 Cov.: 32 AF XY: 0.00334 AC XY: 249 AN XY: 74460

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.00575

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00511 Hom.: 4

Bravo AF: 0.00299

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00312 AC: 379

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00528

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 28, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ALDH5A1: BS2 -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

ALDH5A1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.83	L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.74	N;N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.019	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.27
MVP		0.80
MPC		0.36
ClinPred		0.010	T
GERP RS		5.5
Varity_R		0.57
gMVP		0.62

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: rs115784602; hg19: chr6-24520719; COSMIC: COSV100708715; COSMIC: COSV100708715;