rs756763728

Variant names:

• chr6-24495047-G-A
• rs756763728
• NM_001080.3:c.51G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The ENST00000357578.8(ALDH5A1):​c.51G>A​(p.Ser17Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,355,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: ALDH5A1 ENST00000357578.8 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.254
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 6-24495047-G-A is Benign according to our data. Variant chr6-24495047-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 529491.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.254 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000357578.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.51G>A	p.Ser17Ser	synonymous	Exon 1 of 10	NP_001071.1
	ALDH5A1	NM_170740.1		c.51G>A	p.Ser17Ser	synonymous	Exon 1 of 11	NP_733936.1
	ALDH5A1	NM_001368954.1		c.51G>A	p.Ser17Ser	synonymous	Exon 1 of 9	NP_001355883.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.51G>A	p.Ser17Ser	synonymous	Exon 1 of 10	ENSP00000350191.3
	ALDH5A1	ENST00000348925.2	TSL:1	c.51G>A	p.Ser17Ser	synonymous	Exon 1 of 11	ENSP00000314649.3
	ALDH5A1	ENST00000491546.5	TSL:5	c.51G>A	p.Ser17Ser	synonymous	Exon 1 of 9	ENSP00000417687.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 79922 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000415 AC: 50 AN: 1203624 Hom.: 0 Cov.: 31 AF XY: 0.0000375 AC XY: 22 AN XY: 586412

African (AFR) AF: 0.00 AC: 0 AN: 25548

American (AMR) AF: 0.00 AC: 0 AN: 20380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17978

East Asian (EAS) AF: 0.00 AC: 0 AN: 29830

South Asian (SAS) AF: 0.00 AC: 0 AN: 42356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3312

European-Non Finnish (NFE) AF: 0.0000496 AC: 49 AN: 988456

Other (OTH) AF: 0.0000207 AC: 1 AN: 48366

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Succinate-semialdehyde dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.1
DANN	Benign	0.86
PhyloP100		-0.25
PromoterAI		0.056	Neutral

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: rs756763728; hg19: chr6-24495275;