chr6-24494998-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001080.3(ALDH5A1):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000038 in 1,315,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 8.6e-7 ( 0 hom. )

Consequence

ALDH5A1
NM_001080.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.592

Publications

1 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 links:

GPLD1 (HGNC:4459): (glycosylphosphatidylinositol specific phospholipase D1) Many proteins are tethered to the extracellular face of eukaryotic plasma membranes by a glycosylphosphatidylinositol (GPI) anchor. The GPI-anchor is a glycolipid found on many blood cells. The protein encoded by this gene is a GPI degrading enzyme. Glycosylphosphatidylinositol specific phospholipase D1 hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans, thereby releasing the attached protein from the plasma membrane. [provided by RefSeq, Jul 2008]

GPLD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 15 pathogenic variants. Next in-frame start position is after 89 codons. Genomic position: 24495261. Lost 0.165 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	ENST00000357578.8	NP_001071.1	P51649-1X5DQN2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	1	NM_001080.3	ENSP00000350191.3		P51649-1

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151612

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.59e-7

AC:

AN:

1163682

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

561468

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000406

AC:

AN:

24656

American (AMR)

AF:

0.00

AC:

AN:

17088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15474

East Asian (EAS)

AF:

0.00

AC:

AN:

30122

South Asian (SAS)

AF:

0.00

AC:

AN:

34146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26724

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3126

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

965842

Other (OTH)

AF:

0.00

AC:

AN:

46504

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151612

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74058

show subpopulations

African (AFR)

AF:

0.0000726

AC:

AN:

41304

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000196

AC:

AN:

5096

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67850

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency

Uncertain:1

Mar 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with ALDH5A1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change affects the initiator methionine of the ALDH5A1 mRNA. The next in-frame methionine is located at codon 89. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.12

T;T;.

Eigen

Benign

0.065

Eigen_PC

Benign

0.045

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

-0.080

PhyloP100

0.59

PROVEAN

Benign

-0.42

N;N;N

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.46

P;.;.

Vest4

0.51

MutPred

0.95

Gain of disorder (P = 0.0469);Gain of disorder (P = 0.0469);Gain of disorder (P = 0.0469);

MVP

0.94

ClinPred

0.87

GERP RS

2.4

PromoterAI

-0.56

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.63

Mutation Taster

=9/191

disease causing

(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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chr6-24494998-T-C

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