rs114082057

Variant names:

• chr6-24504988-G-A
• rs114082057
• NM_001080.3:c.726+3G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-24504988-G-A
• chr6-24504988-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001080.3(ALDH5A1):​c.726+3G>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 0.0211 in 1,613,416 control chromosomes in the GnomAD database, including 457 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 0.015 (31 hom., cov: 33)
  • Exomes 𝑓: 0.022 (426 hom.)
• Consequence: ALDH5A1 NM_001080.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005951
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.50
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 6-24504988-G-A is Benign according to our data. Variant chr6-24504988-G-A is described in ClinVar as Benign. ClinVar VariationId is 356134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0149 (2277/152318) while in subpopulation SAS AF = 0.0369 (178/4828). AF 95% confidence interval is 0.0324. There are 31 homozygotes in GnomAd4. There are 1116 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.726+3G>A		splice_region_variant, intron_variant	Intron 4 of 9	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.726+3G>A		splice_region_variant, intron_variant	Intron 4 of 10		NP_733936.1
ALDH5A1	NM_001368954.1	c.726+3G>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+3G>A		splice_region_variant, intron_variant	Intron 4 of 9	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2274 AN: 152200 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0364

Gnomad FIN AF: 0.0229

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0196 AC: 4926 AN: 251312 AF XY: 0.0209

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00601

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0217 AC: 31698 AN: 1461098 Hom.: 426 Cov.: 32 AF XY: 0.0223 AC XY: 16213 AN XY: 726914

African (AFR) AF: 0.00290 AC: 97 AN: 33460

American (AMR) AF: 0.00575 AC: 257 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 310 AN: 26134

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39694

South Asian (SAS) AF: 0.0379 AC: 3268 AN: 86236

European-Finnish (FIN) AF: 0.0295 AC: 1573 AN: 53368

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5766

European-Non Finnish (NFE) AF: 0.0226 AC: 25146 AN: 1111338

Other (OTH) AF: 0.0159 AC: 957 AN: 60378

GnomAD4 genome AF: 0.0149 AC: 2277 AN: 152318 Hom.: 31 Cov.: 33 AF XY: 0.0150 AC XY: 1116 AN XY: 74476

African (AFR) AF: 0.00274 AC: 114 AN: 41580

American (AMR) AF: 0.00680 AC: 104 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00894 AC: 31 AN: 3466

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5182

South Asian (SAS) AF: 0.0369 AC: 178 AN: 4828

European-Finnish (FIN) AF: 0.0229 AC: 243 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0222 AC: 1509 AN: 68028

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0151 Hom.: 12

Bravo AF: 0.0125

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.0185

EpiControl AF: 0.0215

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Jan 13, 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 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 06, 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	-0.32
CADD	Benign	20
DANN	Benign	0.87
PhyloP100		2.5
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00060
dbscSNV1_RF	Benign	0.020
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: rs114082057; hg19: chr6-24505216;