rs76752785

Variant names:

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

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.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
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.610-5C>T		splice_region intron	N/A	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.610-5C>T		splice_region intron	N/A	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.610-5C>T		splice_region intron	N/A	NP_001355883.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.610-5C>T		splice_region intron	N/A	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.610-5C>T		splice_region intron	N/A	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.553-5C>T		splice_region intron	N/A	ENSP00000529897.1

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

GnomAD2 exomes AF: 0.0173 AC: 4348 AN: 251472 AF XY: 0.0141

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 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

African (AFR) AF: 0.138 AC: 4632 AN: 33450

American (AMR) AF: 0.0229 AC: 1026 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0221 AC: 578 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000835 AC: 72 AN: 86228

European-Finnish (FIN) AF: 0.00277 AC: 148 AN: 53418

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5764

European-Non Finnish (NFE) AF: 0.00928 AC: 10303 AN: 1110730

Other (OTH) AF: 0.0184 AC: 1110 AN: 60334

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

African (AFR) AF: 0.137 AC: 5674 AN: 41508

American (AMR) AF: 0.0283 AC: 432 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10610

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00845 AC: 575 AN: 68010

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

Alfa AF: 0.0291 Hom.: 147

Bravo AF: 0.0520

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00996

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Succinate-semialdehyde dehydrogenase deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		0.49
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs76752785; hg19: chr6-24505092;