rs2744584

Positions:

• chr6-24505126-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
ALDH5A1	NM_001080.3	c.726+141G>A		intron_variant		ENST00000357578.8
ALDH5A1	NM_001368954.1	c.726+141G>A		intron_variant
ALDH5A1	NM_170740.1	c.726+141G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.726+141G>A		intron_variant		1	NM_001080.3	P1

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

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.165

Gnomad4 ASJ exome AF: 0.185

Gnomad4 EAS exome AF: 0.0770

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.306

Gnomad4 NFE exome AF: 0.278

Gnomad4 OTH exome AF: 0.246

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

Gnomad4 AFR AF: 0.271

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.195

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.301

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.232

Alfa AF: 0.271 Hom.: 5255

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.35
DANN	Benign	0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs2744584; hg19: chr6-24505354;