rs200793796

Variant names:

• chr6-24495006-T-C
• rs200793796
• NM_001080.3:c.10T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-24495006-T-C
• chr6-24495006-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001080.3(ALDH5A1):​c.10T>C​(p.Cys4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,167,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. C4G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.102
• 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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41020754).

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.10T>C	p.Cys4Arg	missense	Exon 1 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.10T>C	p.Cys4Arg	missense	Exon 1 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.10T>C	p.Cys4Arg	missense	Exon 1 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.10T>C	p.Cys4Arg	missense	Exon 1 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.10T>C	p.Cys4Arg	missense	Exon 1 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.10T>C	p.Cys4Arg	missense	Exon 1 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000685 AC: 8 AN: 1167272 Hom.: 0 Cov.: 31 AF XY: 0.0000107 AC XY: 6 AN XY: 563338

African (AFR) AF: 0.00 AC: 0 AN: 24808

American (AMR) AF: 0.00 AC: 0 AN: 17142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15730

East Asian (EAS) AF: 0.00 AC: 0 AN: 30326

South Asian (SAS) AF: 0.0000292 AC: 1 AN: 34232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3170

European-Non Finnish (NFE) AF: 0.00000723 AC: 7 AN: 968344

Other (OTH) AF: 0.00 AC: 0 AN: 46780

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.10
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.55	N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.24	B
Vest4		0.35
MutPred		0.55		Gain of disorder (P = 0.0085)
MVP		0.66
MPC		1.3
ClinPred		0.87	D
GERP RS		1.2
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.56
Mutation Taster		=93/7	polymorphism

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: rs200793796; hg19: chr6-24495234;