rs2817220

chr6-24504993-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080.3(ALDH5A1):c.726+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,612,044 control chromosomes in the GnomAD database, including 53,764 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4736 hom., cov: 33)
  • Exomes 𝑓: 0.25 (49028 hom.)
• Consequence: ALDH5A1 NM_001080.3 splice_region, intron
• Scores: Splicing: ADA: 0.00008610
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.118

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-24504993-G-A is Benign according to our data. Variant chr6-24504993-G-A is described in ClinVar as [Benign]. Clinvar id is 356135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24504993-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH5A1	NM_001080.3	c.726+8G>A		splice_region_variant, intron_variant		ENST00000357578.8
ALDH5A1	NM_001368954.1	c.726+8G>A		splice_region_variant, intron_variant
ALDH5A1	NM_170740.1	c.726+8G>A		splice_region_variant, intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37124 AN: 152020 Hom.: 4733 Cov.: 33

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.0983

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.221

GnomAD3 exomes AF: 0.220 AC: 55283 AN: 251196 Hom.: 6673 AF XY: 0.218 AC XY: 29580 AN XY: 135810

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.100

Gnomad SAS exome AF: 0.153

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.253 AC: 369243 AN: 1459904 Hom.: 49028 Cov.: 33 AF XY: 0.249 AC XY: 180958 AN XY: 726410

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.162

Gnomad4 ASJ exome AF: 0.176

Gnomad4 EAS exome AF: 0.0809

Gnomad4 SAS exome AF: 0.151

Gnomad4 FIN exome AF: 0.282

Gnomad4 NFE exome AF: 0.272

Gnomad4 OTH exome AF: 0.241

GnomAD4 genome AF: 0.244 AC: 37171 AN: 152140 Hom.: 4736 Cov.: 33 AF XY: 0.239 AC XY: 17763 AN XY: 74380

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.0987

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.279

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.220

Alfa AF: 0.244 Hom.: 6051

Bravo AF: 0.239

Asia WGS AF: 0.122 AC: 428 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	2.1
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000086
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs2817220; hg19: chr6-24505221; COSMIC: COSV62372795;