6-24495006-T-G

Variant names:

• chr6-24495006-T-G
• rs200793796
• NM_001080.3:c.10T>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 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. 14/20 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
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 0.73405 (below the threshold of 3.09). Trascript score misZ: 0.28023 (below the threshold of 3.09). GenCC associations: The gene is linked to succinic semialdehyde dehydrogenase deficiency.
• 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.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.10T>G	p.Cys4Gly	missense_variant	Exon 1 of 10	ENST00000357578.8	NP_001071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.10T>G	p.Cys4Gly	missense_variant	Exon 1 of 10	1	NM_001080.3	ENSP00000350191.3

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

GnomAD2 exomes AF: 0.00769 AC: 648 AN: 84220 AF XY: 0.00780

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 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

African (AFR) AF: 0.000766 AC: 19 AN: 24808

American (AMR) AF: 0.000700 AC: 12 AN: 17142

Ashkenazi Jewish (ASJ) AF: 0.00629 AC: 99 AN: 15730

East Asian (EAS) AF: 0.00 AC: 0 AN: 30326

South Asian (SAS) AF: 0.0000292 AC: 1 AN: 34232

European-Finnish (FIN) AF: 0.0417 AC: 1114 AN: 26730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3170

European-Non Finnish (NFE) AF: 0.00614 AC: 5949 AN: 968320

Other (OTH) AF: 0.00458 AC: 214 AN: 46776

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

African (AFR) AF: 0.000771 AC: 32 AN: 41510

American (AMR) AF: 0.000981 AC: 15 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.0497 AC: 525 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00727 AC: 494 AN: 67904

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00604 Hom.: 4

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

Sep 03, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 05, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALDH5A1: BS2 -

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ALDH5A1-related disorder Benign:1

Jun 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-0.10
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
PromoterAI		0.092	Neutral
Varity_R		0.66
gMVP		0.54
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs200793796; hg19: chr6-24495234;