chr6-24499323-A-G

Variant names:

• chr6-24499323-A-G
• rs7775073
• NM_001080.3:c.355-3200A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001080.3(ALDH5A1):​c.355-3200A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 151,874 control chromosomes in the GnomAD database, including 8,580 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (8580 hom., cov: 30)
• Consequence: ALDH5A1 NM_001080.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.593
• Publications: 9 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]

ALDH5A1 Gene-Disease associations (from GenCC):

• succinic semialdehyde dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.355-3200A>G		intron_variant	Intron 1 of 9	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.355-3200A>G		intron_variant	Intron 1 of 10		NP_733936.1
ALDH5A1	NM_001368954.1	c.355-3200A>G		intron_variant	Intron 1 of 8		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.355-3200A>G		intron_variant	Intron 1 of 9	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49900 AN: 151756 Hom.: 8564 Cov.: 30

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.298

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.329 AC: 49967 AN: 151874 Hom.: 8580 Cov.: 30 AF XY: 0.322 AC XY: 23908 AN XY: 74226

African (AFR) AF: 0.388 AC: 16072 AN: 41400

American (AMR) AF: 0.221 AC: 3373 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 832 AN: 3472

East Asian (EAS) AF: 0.192 AC: 988 AN: 5138

South Asian (SAS) AF: 0.314 AC: 1511 AN: 4812

European-Finnish (FIN) AF: 0.323 AC: 3404 AN: 10546

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22653 AN: 67940

Other (OTH) AF: 0.302 AC: 636 AN: 2106

Alfa AF: 0.318 Hom.: 14886

Bravo AF: 0.324

Asia WGS AF: 0.275 AC: 959 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.5
DANN	Benign	0.61
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

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: rs7775073; hg19: chr6-24499551;