rs58747567

Variant names:

• chr6-24532164-T-C
• rs58747567
• NM_001080.3:c.1389T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001080.3(ALDH5A1):​c.1389T>C​(p.Asp463Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00928 in 1,613,906 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (100 hom.)
• Consequence: ALDH5A1 NM_001080.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.74
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-24532164-T-C is Benign according to our data. Variant chr6-24532164-T-C is described in ClinVar as Benign. ClinVar VariationId is 287826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.74 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00681 (1037/152322) while in subpopulation NFE AF = 0.0117 (796/68018). AF 95% confidence interval is 0.011. There are 6 homozygotes in GnomAd4. There are 468 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.1389T>C	p.Asp463Asp	synonymous	Exon 9 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.1428T>C	p.Asp476Asp	synonymous	Exon 10 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.1245T>C	p.Asp415Asp	synonymous	Exon 8 of 9	NP_001355883.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.1389T>C	p.Asp463Asp	synonymous	Exon 9 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.1428T>C	p.Asp476Asp	synonymous	Exon 10 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.1371T>C	p.Asp457Asp	synonymous	Exon 10 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes AF: 0.00681 AC: 1037 AN: 152204 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00616 AC: 1549 AN: 251444 AF XY: 0.00623

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00954 AC: 13938 AN: 1461584 Hom.: 100 Cov.: 30 AF XY: 0.00932 AC XY: 6774 AN XY: 727112

African (AFR) AF: 0.00161 AC: 54 AN: 33480

American (AMR) AF: 0.00423 AC: 189 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 80 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39696

South Asian (SAS) AF: 0.00117 AC: 101 AN: 86256

European-Finnish (FIN) AF: 0.00197 AC: 105 AN: 53414

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0116 AC: 12912 AN: 1111726

Other (OTH) AF: 0.00805 AC: 486 AN: 60386

GnomAD4 genome AF: 0.00681 AC: 1037 AN: 152322 Hom.: 6 Cov.: 33 AF XY: 0.00628 AC XY: 468 AN XY: 74488

African (AFR) AF: 0.00221 AC: 92 AN: 41582

American (AMR) AF: 0.00595 AC: 91 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0117 AC: 796 AN: 68018

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

Alfa AF: 0.00908 Hom.: 4

Bravo AF: 0.00732

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0108

EpiControl AF: 0.0108

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.086
DANN	Benign	0.32
PhyloP100		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs58747567; hg19: chr6-24532392; COSMIC: COSV62373265;