rs115784602

Positions:

chr6-24520491-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000357578.8(ALDH5A1):c.961G>A(p.Val321Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 1,614,160 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 20 hom. )

Consequence

ALDH5A1
ENST00000357578.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 3.03

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01294896).

BP6

Variant 6-24520491-G-A is Benign according to our data. Variant chr6-24520491-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284072.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=5}. Variant chr6-24520491-G-A is described in Lovd as [Likely_benign]. Variant chr6-24520491-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00339 (516/152284) while in subpopulation NFE AF= 0.00575 (391/68028). AF 95% confidence interval is 0.00528. There are 3 homozygotes in gnomad4. There are 249 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALDH5A1	NM_001080.3 linkuse as main transcript	c.961G>A	p.Val321Met	missense_variant	6/10	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1 linkuse as main transcript	c.1000G>A	p.Val334Met	missense_variant	7/11		NP_733936.1
ALDH5A1	NM_001368954.1 linkuse as main transcript	c.817G>A	p.Val273Met	missense_variant	5/9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8 linkuse as main transcript	c.961G>A	p.Val321Met	missense_variant	6/10	1	NM_001080.3	ENSP00000350191	P1	P51649-1

Frequencies

GnomAD3 genomes

AF:

0.00338

AC:

514

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00572

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00331

AC:

833

AN:

251464

Hom.:

AF XY:

0.00312

AC XY:

424

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.00863

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00407

Gnomad NFE exome

AF:

0.00482

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00480

AC:

7017

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00468

AC XY:

3406

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.00746

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000812

Gnomad4 FIN exome

AF:

0.00387

Gnomad4 NFE exome

AF:

0.00562

Gnomad4 OTH exome

AF:

0.00320

GnomAD4 genome

AF:

0.00339

AC:

516

AN:

152284

Hom.:

Cov.:

AF XY:

0.00334

AC XY:

249

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00311

Gnomad4 NFE

AF:

0.00575

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00511

Hom.:

Bravo

AF:

0.00299

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00312

AC:

379

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00491

EpiControl

AF:

0.00528

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 28, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ALDH5A1: BS2 -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 14, 2020	- -

Succinate-semialdehyde dehydrogenase deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely 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 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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

0.83

L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.74

N;N;N

REVEL

Uncertain

0.42

Sift

Uncertain

0.019

D;D;D

Sift4G

Uncertain

0.021

D;D;D

Polyphen

0.99

D;.;.

Vest4

0.27

MVP

0.80

MPC

0.36

ClinPred

0.010

GERP RS

5.5

Varity_R

0.57

gMVP

0.62

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