rs147358733

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_001080.3(ALDH5A1):c.1198G>A(p.Val400Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,614,026 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 1 hom. )

Consequence

ALDH5A1
NM_001080.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.35

Publications

5 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 -8 ACMG points.

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=0.011430651).

BP6

Variant 6-24528021-G-A is Benign according to our data. Variant chr6-24528021-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286690.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000972 (148/152268) while in subpopulation AFR AF = 0.00337 (140/41566). AF 95% confidence interval is 0.00291. There are 0 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ALDH5A1	NM_001080.3 link	c.1198G>A	p.Val400Ile	missense_variant	Exon 8 of 10	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1 link	c.1237G>A	p.Val413Ile	missense_variant	Exon 9 of 11		NP_733936.1
ALDH5A1	NM_001368954.1 link	c.1054G>A	p.Val352Ile	missense_variant	Exon 7 of 9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8 link	c.1198G>A	p.Val400Ile	missense_variant	Exon 8 of 10	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes

AF:

0.000973

AC:

148

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000195

AC:

AN:

251402

AF XY:

0.0000957

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000958

AC:

140

AN:

1461758

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00311

AC:

104

AN:

33478

American (AMR)

AF:

0.000246

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111938

Other (OTH)

AF:

0.000215

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000972

AC:

148

AN:

152268

Hom.:

Cov.:

AF XY:

0.000940

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00337

AC:

140

AN:

41566

American (AMR)

AF:

0.000262

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68012

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000386

Hom.:

Bravo

AF:

0.00104

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000280

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Mar 22, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 05, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Succinate-semialdehyde dehydrogenase deficiency

Uncertain:1Benign:1

Jan 28, 2022

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALDH5A1-related disorder

Benign:1

Sep 07, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.17

T;T;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.4

L;.;.

PhyloP100

3.4

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.30

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.0090

B;.;.

Vest4

0.15

MVP

0.62

MPC

0.22

ClinPred

0.023

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.44

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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