rs887448536

Variant names:

• chr6-24522772-T-G
• rs887448536
• NM_001080.3:c.1020T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-24522772-T-G
• chr6-24522772-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001080.3(ALDH5A1):​c.1020T>G​(p.Cys340Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,690 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C340S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.580
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.1020T>G	p.Cys340Trp	missense	Exon 7 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.1059T>G	p.Cys353Trp	missense	Exon 8 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.876T>G	p.Cys292Trp	missense	Exon 6 of 9	NP_001355883.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.1020T>G	p.Cys340Trp	missense	Exon 7 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.1059T>G	p.Cys353Trp	missense	Exon 8 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.1002T>G	p.Cys334Trp	missense	Exon 8 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461690 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111900

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Succinate-semialdehyde dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		0.58
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.84		Gain of MoRF binding (P = 0.0126)
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		-5.4
Varity_R		0.99
gMVP		0.98
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs887448536; hg19: chr6-24523000;