rs2744601

Variant names:

• chr6-24533277-G-C
• rs2744601
• NM_001080.3:c.1403-230G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001080.3(ALDH5A1):​c.1403-230G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 152,142 control chromosomes in the GnomAD database, including 1,379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.13 (1379 hom., cov: 32)
• Consequence: ALDH5A1 NM_001080.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.323
• 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-24533277-G-C is Benign according to our data. Variant chr6-24533277-G-C is described in ClinVar as Benign. ClinVar VariationId is 1249324.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.1403-230G>C		intron_variant	Intron 9 of 9	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.1442-230G>C		intron_variant	Intron 10 of 10		NP_733936.1
ALDH5A1	NM_001368954.1	c.1259-230G>C		intron_variant	Intron 8 of 8		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.1403-230G>C		intron_variant	Intron 9 of 9	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19551 AN: 152022 Hom.: 1377 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.0942

Gnomad ASJ AF: 0.0919

Gnomad EAS AF: 0.0665

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.117

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.129 AC: 19576 AN: 152142 Hom.: 1379 Cov.: 32 AF XY: 0.125 AC XY: 9272 AN XY: 74386

African (AFR) AF: 0.103 AC: 4283 AN: 41514

American (AMR) AF: 0.0945 AC: 1445 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0919 AC: 319 AN: 3470

East Asian (EAS) AF: 0.0667 AC: 345 AN: 5176

South Asian (SAS) AF: 0.118 AC: 566 AN: 4812

European-Finnish (FIN) AF: 0.138 AC: 1465 AN: 10586

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10709 AN: 67980

Other (OTH) AF: 0.117 AC: 248 AN: 2112

Alfa AF: 0.141 Hom.: 225

Bravo AF: 0.124

Asia WGS AF: 0.0870 AC: 305 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.92
CADD	Benign	3.3
DANN	Benign	0.65
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2744601; hg19: chr6-24533505;