chr6-24522915-C-A

Variant names:

• chr6-24522915-C-A
• NM_001080.3:c.1163C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001080.3(ALDH5A1):​c.1163C>A​(p.Ala388Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A388A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.1163C>A	p.Ala388Glu	missense_variant	Exon 7 of 10	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.1202C>A	p.Ala401Glu	missense_variant	Exon 8 of 11		NP_733936.1
ALDH5A1	NM_001368954.1	c.1019C>A	p.Ala340Glu	missense_variant	Exon 6 of 9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.1163C>A	p.Ala388Glu	missense_variant	Exon 7 of 10	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency Uncertain:1

Jul 06, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.64		Gain of disorder (P = 0.043);.;.;
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-24523143;