rs2744584

Variant names:

• chr6-24505126-G-A
• rs2744584
• NM_001080.3:c.726+141G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001080.3(ALDH5A1):​c.726+141G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 874,754 control chromosomes in the GnomAD database, including 30,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5373 hom., cov: 33)
  • Exomes 𝑓: 0.25 (24779 hom.)
• Consequence: ALDH5A1 NM_001080.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.694
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-24505126-G-A is Benign according to our data. Variant chr6-24505126-G-A is described in ClinVar as Benign. ClinVar VariationId is 1237142.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.726+141G>A		intron_variant	Intron 4 of 9	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.726+141G>A		intron_variant	Intron 4 of 10		NP_733936.1
ALDH5A1	NM_001368954.1	c.726+141G>A		intron_variant	Intron 4 of 8		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.726+141G>A		intron_variant	Intron 4 of 9	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39489 AN: 152008 Hom.: 5369 Cov.: 33

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.250 AC: 180430 AN: 722626 Hom.: 24779 AF XY: 0.247 AC XY: 94149 AN XY: 381606

African (AFR) AF: 0.255 AC: 4952 AN: 19432

American (AMR) AF: 0.165 AC: 6159 AN: 37368

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 3839 AN: 20712

East Asian (EAS) AF: 0.0770 AC: 2735 AN: 35506

South Asian (SAS) AF: 0.186 AC: 12580 AN: 67704

European-Finnish (FIN) AF: 0.306 AC: 11255 AN: 36736

Middle Eastern (MID) AF: 0.120 AC: 452 AN: 3756

European-Non Finnish (NFE) AF: 0.278 AC: 129528 AN: 465168

Other (OTH) AF: 0.246 AC: 8930 AN: 36244

GnomAD4 genome AF: 0.260 AC: 39537 AN: 152128 Hom.: 5373 Cov.: 33 AF XY: 0.255 AC XY: 18925 AN XY: 74352

African (AFR) AF: 0.271 AC: 11223 AN: 41484

American (AMR) AF: 0.181 AC: 2775 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 676 AN: 3468

East Asian (EAS) AF: 0.101 AC: 522 AN: 5180

South Asian (SAS) AF: 0.185 AC: 893 AN: 4826

European-Finnish (FIN) AF: 0.301 AC: 3185 AN: 10568

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19377 AN: 67994

Other (OTH) AF: 0.232 AC: 491 AN: 2112

Alfa AF: 0.271 Hom.: 6376

Bravo AF: 0.252

Asia WGS AF: 0.146 AC: 511 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.35
DANN	Benign	0.33
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2744584; hg19: chr6-24505354;