6-24503369-C-T

Position:

chr6-24503369-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001080.3(ALDH5A1):c.545C>T(p.Pro182Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0302 in 1,613,974 control chromosomes in the GnomAD database, including 1,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P182V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.029 ( 100 hom., cov: 32)

Exomes 𝑓: 0.030 ( 1192 hom. )

Consequence

ALDH5A1
NM_001080.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.92

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 -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001080.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0026880205).

BP6

Variant 6-24503369-C-T is Benign according to our data. Variant chr6-24503369-C-T is described in ClinVar as [Benign]. Clinvar id is 128344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24503369-C-T is described in Lovd as [Benign]. Variant chr6-24503369-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALDH5A1	NM_001080.3 linkuse as main transcript	c.545C>T	p.Pro182Leu	missense_variant	3/10	ENST00000357578.8
ALDH5A1	NM_170740.1 linkuse as main transcript	c.545C>T	p.Pro182Leu	missense_variant	3/11
ALDH5A1	NM_001368954.1 linkuse as main transcript	c.545C>T	p.Pro182Leu	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8 linkuse as main transcript	c.545C>T	p.Pro182Leu	missense_variant	3/10	1	NM_001080.3	P1	P51649-1

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

4336

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.0222

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.0829

Gnomad SAS

AF:

0.0998

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0251

Gnomad OTH

AF:

0.0287

GnomAD3 exomes

AF:

0.0380

AC:

9539

AN:

251096

Hom.:

298

AF XY:

0.0410

AC XY:

5570

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.0206

Gnomad AMR exome

AF:

0.0217

Gnomad ASJ exome

AF:

0.0302

Gnomad EAS exome

AF:

0.0803

Gnomad SAS exome

AF:

0.102

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.0256

Gnomad OTH exome

AF:

0.0347

GnomAD4 exome

AF:

0.0304

AC:

44435

AN:

1461642

Hom.:

1192

Cov.:

AF XY:

0.0324

AC XY:

23590

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.0251

Gnomad4 AMR exome

AF:

0.0216

Gnomad4 ASJ exome

AF:

0.0281

Gnomad4 EAS exome

AF:

0.0962

Gnomad4 SAS exome

AF:

0.0993

Gnomad4 FIN exome

AF:

0.0216

Gnomad4 NFE exome

AF:

0.0233

Gnomad4 OTH exome

AF:

0.0355

GnomAD4 genome

AF:

0.0285

AC:

4345

AN:

152332

Hom.:

100

Cov.:

AF XY:

0.0290

AC XY:

2160

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0230

Gnomad4 AMR

AF:

0.0222

Gnomad4 ASJ

AF:

0.0271

Gnomad4 EAS

AF:

0.0831

Gnomad4 SAS

AF:

0.0988

Gnomad4 FIN

AF:

0.0162

Gnomad4 NFE

AF:

0.0251

Gnomad4 OTH

AF:

0.0345

Alfa

AF:

0.0293

Hom.:

165

Bravo

AF:

0.0275

TwinsUK

AF:

0.0208

AC:

ALSPAC

AF:

0.0246

AC:

ESP6500AA

AF:

0.0241

AC:

106

ESP6500EA

AF:

0.0273

AC:

235

ExAC

AF:

0.0401

AC:

4866

Asia WGS

AF:

0.109

AC:

379

AN:

3478

EpiCase

AF:

0.0281

EpiControl

AF:

0.0276

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Succinate-semialdehyde dehydrogenase deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

ALDH5A1-related disorder

Benign:1

Benign, no assertion criteria provided

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: 12208142, 27056292, 19164088) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;T;.

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

D;D;D

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.4

L;.;L

MutationTaster

Benign

0.70

D;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-5.2

D;D;D

REVEL

Uncertain

0.30

Sift

Benign

0.11

T;T;T

Sift4G

Uncertain

0.041

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.22

MPC

0.68

ClinPred

0.024

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.34

gMVP

0.72

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