rs4646832

Positions:

chr6-24495102-G-C

Variant summary

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

The NM_001080.3(ALDH5A1):c.106G>C(p.Gly36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,315,212 control chromosomes in the GnomAD database, including 855 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 104 hom., cov: 33)

Exomes 𝑓: 0.028 ( 751 hom. )

Consequence

ALDH5A1
NM_001080.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.00800

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:

GPLD1 (HGNC:4459): (glycosylphosphatidylinositol specific phospholipase D1) Many proteins are tethered to the extracellular face of eukaryotic plasma membranes by a glycosylphosphatidylinositol (GPI) anchor. The GPI-anchor is a glycolipid found on many blood cells. The protein encoded by this gene is a GPI degrading enzyme. Glycosylphosphatidylinositol specific phospholipase D1 hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans, thereby releasing the attached protein from the plasma membrane. [provided by RefSeq, Jul 2008]

GPLD1 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 (MetaRNN=0.0016960204).

BP6

Variant 6-24495102-G-C is Benign according to our data. Variant chr6-24495102-G-C is described in ClinVar as [Benign]. Clinvar id is 285783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24495102-G-C is described in Lovd as [Benign]. Variant chr6-24495102-G-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.091 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH5A1	NM_001080.3 linkuse as main transcript	c.106G>C	p.Gly36Arg	missense_variant	1/10	ENST00000357578.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8 linkuse as main transcript	c.106G>C	p.Gly36Arg	missense_variant	1/10	1	NM_001080.3	P1	P51649-1

Frequencies

GnomAD3 genomes

AF:

0.0276

AC:

4184

AN:

151744

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.0827

Gnomad SAS

AF:

0.0991

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.0541

Gnomad NFE

AF:

0.0254

Gnomad OTH

AF:

0.0260

GnomAD3 exomes

AF:

0.0407

AC:

500

AN:

12294

Hom.:

AF XY:

0.0450

AC XY:

347

AN XY:

7704

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0321

Gnomad EAS exome

AF:

0.0616

Gnomad SAS exome

AF:

0.102

Gnomad FIN exome

AF:

0.0159

Gnomad NFE exome

AF:

0.0220

Gnomad OTH exome

AF:

0.0505

GnomAD4 exome

AF:

0.0280

AC:

32598

AN:

1163360

Hom.:

751

Cov.:

AF XY:

0.0288

AC XY:

16250

AN XY:

563270

show subpopulations

Gnomad4 AFR exome

AF:

0.0218

Gnomad4 AMR exome

AF:

0.0220

Gnomad4 ASJ exome

AF:

0.0277

Gnomad4 EAS exome

AF:

0.104

Gnomad4 SAS exome

AF:

0.0941

Gnomad4 FIN exome

AF:

0.0222

Gnomad4 NFE exome

AF:

0.0233

Gnomad4 OTH exome

AF:

0.0342

GnomAD4 genome

AF:

0.0276

AC:

4192

AN:

151852

Hom.:

104

Cov.:

AF XY:

0.0283

AC XY:

2098

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.0194

Gnomad4 AMR

AF:

0.0218

Gnomad4 ASJ

AF:

0.0271

Gnomad4 EAS

AF:

0.0832

Gnomad4 SAS

AF:

0.0983

Gnomad4 FIN

AF:

0.0165

Gnomad4 NFE

AF:

0.0254

Gnomad4 OTH

AF:

0.0314

Alfa

AF:

0.0272

Hom.:

Bravo

AF:

0.0264

ExAC

AF:

0.0287

AC:

836

Asia WGS

AF:

0.106

AC:

365

AN:

3444

ClinVar

Significance: Benign

Submissions summary: Benign:5

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 13, 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	Invitae	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 29, 2016

- -

ALDH5A1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 07, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

This variant is associated with the following publications: (PMID: 19164088, 27056292) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.50

CADD

Benign

1.3

DANN

Benign

0.62

DEOGEN2

Benign

0.31

T;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0061

LIST_S2

Benign

0.49

T;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

N;.;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.030

N;N;N

REVEL

Benign

0.10

Sift

Benign

0.85

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.091

MutPred

0.099

Gain of methylation at G36 (P = 0.0093);Gain of methylation at G36 (P = 0.0093);Gain of methylation at G36 (P = 0.0093);

MPC

0.32

ClinPred

0.0043

GERP RS

-6.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.045

gMVP

0.38

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

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