rs147439442

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_001080.3(ALDH5A1):c.542C>A(p.Thr181Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T181I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ALDH5A1
NM_001080.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.94

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_001080.3

PM2

Very rare variant in population databases, with high coverage;

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=0.15381676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ALDH5A1	NM_001080.3 link	c.542C>A	p.Thr181Asn	missense_variant	Exon 3 of 10	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1 link	c.542C>A	p.Thr181Asn	missense_variant	Exon 3 of 11		NP_733936.1
ALDH5A1	NM_001368954.1 link	c.542C>A	p.Thr181Asn	missense_variant	Exon 3 of 9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8 link	c.542C>A	p.Thr181Asn	missense_variant	Exon 3 of 10	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111988

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.24

T;T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.47

N;.;N

PhyloP100

3.9

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.063

T;T;T

Sift4G

Uncertain

0.048

D;D;D

Polyphen

0.83

P;.;.

Vest4

0.29

MutPred

0.35

Loss of phosphorylation at T181 (P = 0.0726);.;Loss of phosphorylation at T181 (P = 0.0726);

MVP

0.77

MPC

0.31

ClinPred

0.56

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.36

gMVP

0.62

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over