rs774379306

Variant names:

• chr6-24495016-T-G
• rs774379306
• NM_001080.3:c.20T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001080.3(ALDH5A1):​c.20T>G​(p.Leu7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,176,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L7L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.443
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

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.20T>G	p.Leu7Arg	missense	Exon 1 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.20T>G	p.Leu7Arg	missense	Exon 1 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.20T>G	p.Leu7Arg	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.20T>G	p.Leu7Arg	missense	Exon 1 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.20T>G	p.Leu7Arg	missense	Exon 1 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.20T>G	p.Leu7Arg	missense	Exon 1 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 1 AN: 82888 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000425 AC: 5 AN: 1176142 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 569256

African (AFR) AF: 0.00 AC: 0 AN: 24920

American (AMR) AF: 0.00 AC: 0 AN: 17324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16010

East Asian (EAS) AF: 0.00 AC: 0 AN: 30434

South Asian (SAS) AF: 0.00 AC: 0 AN: 35564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3180

European-Non Finnish (NFE) AF: 0.00000513 AC: 5 AN: 974564

Other (OTH) AF: 0.00 AC: 0 AN: 47150

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000893 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Succinate-semialdehyde dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.44
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0020	B
Vest4		0.66
MutPred		0.51		Gain of disorder (P = 0.0028)
MVP		0.70
MPC		1.1
ClinPred		0.50	D
GERP RS		1.3
PromoterAI		0.054	Neutral
Varity_R		0.34
gMVP		0.66
Mutation Taster		=96/4	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: rs774379306; hg19: chr6-24495244;