NM_001080.3:c.10T>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 Benign/Likely_benign. ClinVar VariationId 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.10T>G	p.Cys4Gly	missense	Exon 1 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.10T>G	p.Cys4Gly	missense	Exon 1 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.10T>G	p.Cys4Gly	missense	Exon 1 of 9	NP_001355883.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.10T>G	p.Cys4Gly	missense	Exon 1 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.10T>G	p.Cys4Gly	missense	Exon 1 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.10T>G	p.Cys4Gly	missense	Exon 1 of 11	ENSP00000529897.1

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Succinate-semialdehyde dehydrogenase deficiency (2)
-	-	1	ALDH5A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.10
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	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;