chr6-24495033-C-T

Variant names:

• chr6-24495033-C-T
• rs766443938
• NM_001080.3:c.37C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001080.3(ALDH5A1):​c.37C>T​(p.Arg13Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000167 in 1,195,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.224
• 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 1 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=0.16822436).

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.37C>T	p.Arg13Trp	missense	Exon 1 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.37C>T	p.Arg13Trp	missense	Exon 1 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.37C>T	p.Arg13Trp	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.37C>T	p.Arg13Trp	missense	Exon 1 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.37C>T	p.Arg13Trp	missense	Exon 1 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.37C>T	p.Arg13Trp	missense	Exon 1 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000117 AC: 1 AN: 85558 AF XY: 0.0000201

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000167 AC: 2 AN: 1195698 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 581320

African (AFR) AF: 0.00 AC: 0 AN: 25406

American (AMR) AF: 0.000102 AC: 2 AN: 19626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17242

East Asian (EAS) AF: 0.00 AC: 0 AN: 30234

South Asian (SAS) AF: 0.00 AC: 0 AN: 39662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 984838

Other (OTH) AF: 0.00 AC: 0 AN: 48062

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000903 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Succinate-semialdehyde dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.22
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.24
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.026	D
Polyphen		0.96	D
Vest4		0.12
MutPred		0.36		Loss of disorder (P = 5e-04)
MVP		0.86
MPC		0.52
ClinPred		0.49	T
GERP RS		1.4
PromoterAI		0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.079
gMVP		0.42
Mutation Taster		=98/2	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: rs766443938; hg19: chr6-24495261;