rs2817220

Positions:

chr6-24504993-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001080.3(ALDH5A1):c.726+8G>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 0.252 in 1,612,044 control chromosomes in the GnomAD database, including 53,764 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 0.24 ( 4736 hom., cov: 33)

Exomes 𝑓: 0.25 ( 49028 hom. )

Consequence

ALDH5A1
NM_001080.3 splice_region, intron

Scores

Splicing: ADA: 0.00008610

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.118

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 6-24504993-G-A is Benign according to our data. Variant chr6-24504993-G-A is described in ClinVar as [Benign]. Clinvar id is 356135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24504993-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
ALDH5A1	NM_001080.3 linkuse as main transcript	c.726+8G>A	splice_region_variant, intron_variant	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_001368954.1 linkuse as main transcript	c.726+8G>A	splice_region_variant, intron_variant		NP_001355883.1
ALDH5A1	NM_170740.1 linkuse as main transcript	c.726+8G>A	splice_region_variant, intron_variant		NP_733936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8 linkuse as main transcript	c.726+8G>A		splice_region_variant, intron_variant		1	NM_001080.3	ENSP00000350191	P1	P51649-1

Frequencies

GnomAD3 genomes

AF:

0.244

AC:

37124

AN:

152020

Hom.:

4733

Cov.:

show subpopulations

Gnomad AFR

AF:

0.267

Gnomad AMI

AF:

0.312

Gnomad AMR

AF:

0.173

Gnomad ASJ

AF:

0.183

Gnomad EAS

AF:

0.0983

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.279

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.263

Gnomad OTH

AF:

0.221

GnomAD3 exomes

AF:

0.220

AC:

55283

AN:

251196

Hom.:

6673

AF XY:

0.218

AC XY:

29580

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.267

Gnomad AMR exome

AF:

0.158

Gnomad ASJ exome

AF:

0.173

Gnomad EAS exome

AF:

0.100

Gnomad SAS exome

AF:

0.153

Gnomad FIN exome

AF:

0.281

Gnomad NFE exome

AF:

0.262

Gnomad OTH exome

AF:

0.219

GnomAD4 exome

AF:

0.253

AC:

369243

AN:

1459904

Hom.:

49028

Cov.:

AF XY:

0.249

AC XY:

180958

AN XY:

726410

show subpopulations

Gnomad4 AFR exome

AF:

0.257

Gnomad4 AMR exome

AF:

0.162

Gnomad4 ASJ exome

AF:

0.176

Gnomad4 EAS exome

AF:

0.0809

Gnomad4 SAS exome

AF:

0.151

Gnomad4 FIN exome

AF:

0.282

Gnomad4 NFE exome

AF:

0.272

Gnomad4 OTH exome

AF:

0.241

GnomAD4 genome

AF:

0.244

AC:

37171

AN:

152140

Hom.:

4736

Cov.:

AF XY:

0.239

AC XY:

17763

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.267

Gnomad4 AMR

AF:

0.173

Gnomad4 ASJ

AF:

0.183

Gnomad4 EAS

AF:

0.0987

Gnomad4 SAS

AF:

0.147

Gnomad4 FIN

AF:

0.279

Gnomad4 NFE

AF:

0.263

Gnomad4 OTH

AF:

0.220

Alfa

AF:

0.244

Hom.:

6051

Bravo

AF:

0.239

Asia WGS

AF:

0.122

AC:

428

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.1

DANN

Benign

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000086

dbscSNV1_RF

Benign

0.0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over