rs200793796

chr6-24495006-T-G

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.10T>G(p.Cys4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,319,228 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. C4C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0071 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (44 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.102

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020737946).
• BP6: Variant 6-24495006-T-G is Benign according to our data. Variant chr6-24495006-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 288703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24495006-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00715 (1086/151994) while in subpopulation NFE AF= 0.00727 (494/67904). AF 95% confidence interval is 0.00674. There are 15 homozygotes in gnomad4. There are 620 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH5A1	NM_001080.3	c.10T>G	p.Cys4Gly	missense_variant	1/10	ENST00000357578.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.10T>G	p.Cys4Gly	missense_variant	1/10	1	NM_001080.3	P1

Frequencies

GnomAD3 genomes AF: 0.00715 AC: 1086 AN: 151878 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0497

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00727

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00769 AC: 648 AN: 84220 Hom.: 7 AF XY: 0.00780 AC XY: 379 AN XY: 48562

Gnomad AFR exome AF: 0.000658

Gnomad AMR exome AF: 0.000218

Gnomad ASJ exome AF: 0.00332

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0370

Gnomad NFE exome AF: 0.00910

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.00635 AC: 7408 AN: 1167234 Hom.: 44 Cov.: 31 AF XY: 0.00632 AC XY: 3560 AN XY: 563324

Gnomad4 AFR exome AF: 0.000766

Gnomad4 AMR exome AF: 0.000700

Gnomad4 ASJ exome AF: 0.00629

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000292

Gnomad4 FIN exome AF: 0.0417

Gnomad4 NFE exome AF: 0.00614

Gnomad4 OTH exome AF: 0.00458

GnomAD4 genome AF: 0.00715 AC: 1086 AN: 151994 Hom.: 15 Cov.: 33 AF XY: 0.00834 AC XY: 620 AN XY: 74304

Gnomad4 AFR AF: 0.000771

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0497

Gnomad4 NFE AF: 0.00727

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00572 Hom.: 2

Bravo AF: 0.00343

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000336 AC: 1

ESP6500EA AF: 0.00305 AC: 20

ExAC AF: 0.00694 AC: 780

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ALDH5A1: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -

Succinate-semialdehyde dehydrogenase deficiency Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

ALDH5A1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

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	0.065
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	20
Dann	Benign	0.95
DEOGEN2	Benign	0.14	T;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.67	T;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0	B;.;.
Vest4		0.45
MVP		0.56
MPC		1.0
ClinPred		0.076	T
GERP RS		1.2
Varity_R		0.66
gMVP		0.54

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: rs200793796; hg19: chr6-24495234;