rs76752785

Variant names:

• chr6-24504864-C-T
• rs76752785
• NM_001080.3:c.610-5C>T

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.610-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,612,674 control chromosomes in the GnomAD database, including 836 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 0.045 (384 hom., cov: 33)
  • Exomes 𝑓: 0.012 (452 hom.)
• Consequence: ALDH5A1 NM_001080.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006809
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.493

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=-0.76).
• BP6: Variant 6-24504864-C-T is Benign according to our data. Variant chr6-24504864-C-T is described in ClinVar as [Benign]. Clinvar id is 356133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.610-5C>T		splice_region_variant, intron_variant	Intron 3 of 9	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.610-5C>T		splice_region_variant, intron_variant	Intron 3 of 10		NP_733936.1
ALDH5A1	NM_001368954.1	c.610-5C>T		splice_region_variant, intron_variant	Intron 3 of 8		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.610-5C>T		splice_region_variant, intron_variant	Intron 3 of 9	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes AF: 0.0451 AC: 6855 AN: 152090 Hom.: 384 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00845

Gnomad OTH AF: 0.0359

GnomAD3 exomes AF: 0.0173 AC: 4348 AN: 251472 Hom.: 189 AF XY: 0.0141 AC XY: 1915 AN XY: 135914

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00300

Gnomad NFE exome AF: 0.00779

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.0123 AC: 17936 AN: 1460466 Hom.: 452 Cov.: 32 AF XY: 0.0114 AC XY: 8296 AN XY: 726652

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.0229

Gnomad4 ASJ exome AF: 0.0221

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.00277

Gnomad4 NFE exome AF: 0.00928

Gnomad4 OTH exome AF: 0.0184

GnomAD4 genome AF: 0.0452 AC: 6873 AN: 152208 Hom.: 384 Cov.: 33 AF XY: 0.0437 AC XY: 3253 AN XY: 74434

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0283

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00845

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.0270 Hom.: 100

Bravo AF: 0.0520

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00996

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:1

Jul 17, 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	-0.76
CADD	Benign	11
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000068
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.060		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: rs76752785; hg19: chr6-24505092;