NM_001080.3:c.1348G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001080.3(ALDH5A1):c.1348G>A(p.Asp450Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,614,096 control chromosomes in the GnomAD database, including 2 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D450E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

ALDH5A1
NM_001080.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 1.57

Publications

4 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 -12 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=0.0119740665).

BP6

Variant 6-24532123-G-A is Benign according to our data. Variant chr6-24532123-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287090.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00202 (307/152294) while in subpopulation AFR AF = 0.00688 (286/41562). AF 95% confidence interval is 0.00623. There are 2 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3 link	c.1348G>A	p.Asp450Asn	missense_variant	Exon 9 of 10	ENST00000357578.8	NP_001071.1	P51649-1X5DQN2
ALDH5A1	NM_170740.1 link	c.1387G>A	p.Asp463Asn	missense_variant	Exon 10 of 11		NP_733936.1	P51649-2X5D299
ALDH5A1	NM_001368954.1 link	c.1204G>A	p.Asp402Asn	missense_variant	Exon 8 of 9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8 link	c.1348G>A	p.Asp450Asn	missense_variant	Exon 9 of 10	1	NM_001080.3	ENSP00000350191.3		P51649-1

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

307

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00690

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000541

AC:

136

AN:

251436

AF XY:

0.000316

show subpopulations

Gnomad AFR exome

AF:

0.00658

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000205

AC:

299

AN:

1461802

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

141

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00624

AC:

209

AN:

33480

American (AMR)

AF:

0.000514

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111940

Other (OTH)

AF:

0.000464

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00202

AC:

307

AN:

152294

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00688

AC:

286

AN:

41562

American (AMR)

AF:

0.000785

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68018

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000771

Hom.:

Bravo

AF:

0.00251

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000782

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Dec 14, 2018

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 12, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 24, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The D450N variant in the ALDH5A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, D450N is reported as likely benign in ClinVar by different clinical laboratories, but additional evidence is not available (ClinVar SCV000340750.2; ClinVar SCV000511533.1; Landrum et al., 2016). This variant is observed in 177/24,038 alleles (0.74%) from individuals of African background in large population cohorts, including 2 homozygous control individuals (Lek et al., 2016). The D450N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D450N as a variant of uncertain significance. -

Succinate-semialdehyde dehydrogenase deficiency

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

ALDH5A1-related disorder

Benign:1

Jun 21, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Sep 01, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.28

T;T;.

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.8

L;.;.

PhyloP100

1.6

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.87

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.26

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.11

MVP

0.78

MPC

0.26

ClinPred

0.018

GERP RS

-0.25

Varity_R

0.16

gMVP

0.42

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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