chr6-24504993-G-A

Variant names:

• chr6-24504993-G-A
• rs2817220
• NM_001080.3:c.726+8G>A

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -0.118
• Publications: 12 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 -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 VariationId is 356135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.726+8G>A		splice_region_variant, intron_variant	Intron 4 of 9	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.726+8G>A		splice_region_variant, intron_variant	Intron 4 of 10		NP_733936.1
ALDH5A1	NM_001368954.1	c.726+8G>A		splice_region_variant, 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+8G>A		splice_region_variant, intron_variant	Intron 4 of 9	1	NM_001080.3	ENSP00000350191.3

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

GnomAD2 exomes AF: 0.220 AC: 55283 AN: 251196 AF XY: 0.218

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 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

African (AFR) AF: 0.257 AC: 8610 AN: 33450

American (AMR) AF: 0.162 AC: 7253 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4585 AN: 26118

East Asian (EAS) AF: 0.0809 AC: 3209 AN: 39690

South Asian (SAS) AF: 0.151 AC: 13011 AN: 86208

European-Finnish (FIN) AF: 0.282 AC: 15016 AN: 53298

Middle Eastern (MID) AF: 0.112 AC: 646 AN: 5760

European-Non Finnish (NFE) AF: 0.272 AC: 302380 AN: 1110336

Other (OTH) AF: 0.241 AC: 14533 AN: 60322

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

African (AFR) AF: 0.267 AC: 11069 AN: 41480

American (AMR) AF: 0.173 AC: 2646 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 637 AN: 3472

East Asian (EAS) AF: 0.0987 AC: 511 AN: 5176

South Asian (SAS) AF: 0.147 AC: 709 AN: 4822

European-Finnish (FIN) AF: 0.279 AC: 2952 AN: 10584

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17857 AN: 67994

Other (OTH) AF: 0.220 AC: 465 AN: 2112

Alfa AF: 0.245 Hom.: 7485

Bravo AF: 0.239

Asia WGS AF: 0.122 AC: 428 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported. -

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	-0.81
CADD	Benign	2.1
DANN	Benign	0.80
PhyloP100		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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