6-24504968-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1PM5PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001080.3(ALDH5A1):c.709G>T(p.Ala237Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,082 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A237T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.012 ( 21 hom., cov: 33)

Exomes 𝑓: 0.015 ( 210 hom. )

Consequence

ALDH5A1
NM_001080.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 9.50

Publications

20 publications found

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 Gene-Disease associations (from GenCC):

succinic semialdehyde dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ALDH5A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001080.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-24504968-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 904924.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 0.73405 (below the threshold of 3.09). Trascript score misZ: 0.28023 (below the threshold of 3.09). GenCC associations: The gene is linked to succinic semialdehyde dehydrogenase deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.012225747).

BP6

Variant 6-24504968-G-T is Benign according to our data. Variant chr6-24504968-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0121 (1847/152302) while in subpopulation NFE AF = 0.0192 (1303/68032). AF 95% confidence interval is 0.0183. There are 21 homozygotes in GnomAd4. There are 833 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3 link	c.709G>T	p.Ala237Ser	missense_variant	Exon 4 of 10	ENST00000357578.8	NP_001071.1	P51649-1X5DQN2
ALDH5A1	NM_170740.1 link	c.709G>T	p.Ala237Ser	missense_variant	Exon 4 of 11		NP_733936.1	P51649-2X5D299
ALDH5A1	NM_001368954.1 link	c.709G>T	p.Ala237Ser	missense_variant	Exon 4 of 9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8 link	c.709G>T	p.Ala237Ser	missense_variant	Exon 4 of 10	1	NM_001080.3	ENSP00000350191.3		P51649-1

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1847

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.00577

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.00801

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0192

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.0114

AC:

2856

AN:

251372

AF XY:

0.0115

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00714

Gnomad ASJ exome

AF:

0.00625

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00781

Gnomad NFE exome

AF:

0.0182

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.0145

AC:

21242

AN:

1461780

Hom.:

210

Cov.:

AF XY:

0.0144

AC XY:

10476

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00278

AC:

AN:

33480

American (AMR)

AF:

0.00745

AC:

333

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00719

AC:

188

AN:

26136

East Asian (EAS)

AF:

0.000277

AC:

AN:

39698

South Asian (SAS)

AF:

0.00674

AC:

581

AN:

86254

European-Finnish (FIN)

AF:

0.00901

AC:

481

AN:

53384

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0167

AC:

18564

AN:

1111944

Other (OTH)

AF:

0.0148

AC:

893

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1175

2349

3524

4698

5873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

612

1224

1836

2448

3060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0121

AC:

1847

AN:

152302

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

833

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00274

AC:

114

AN:

41564

American (AMR)

AF:

0.0124

AC:

190

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00577

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.0120

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00801

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0192

AC:

1303

AN:

68032

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

192

287

383

479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0158

Hom.:

103

Bravo

AF:

0.0120

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0199

AC:

171

ExAC

AF:

0.0119

AC:

1449

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0200

EpiControl

AF:

0.0187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 12, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 21, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Aug 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29895405, 19164088, 12208142) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Succinate-semialdehyde dehydrogenase deficiency

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

2.0

M;.;M

PhyloP100

9.5

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.051

T;T;T

Polyphen

0.68

P;.;.

Vest4

0.60

MPC

0.90

ClinPred

0.031

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.78

gMVP

0.80

Mutation Taster

=56/44

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over