6-24495126-C-G

Variant names:

• chr6-24495126-C-G
• rs185042766
• NM_001080.3:c.130C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080.3(ALDH5A1):​c.130C>G​(p.Leu44Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 1,382,708 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.340
• Publications: 1 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: Benign. The variant received -19 ACMG points.

• 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=0.0041862726).
• BP6: Variant 6-24495126-C-G is Benign according to our data. Variant chr6-24495126-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 356126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00247 (375/151868) while in subpopulation AFR AF = 0.00855 (355/41522). AF 95% confidence interval is 0.00782. There are 1 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.130C>G	p.Leu44Val	missense	Exon 1 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.130C>G	p.Leu44Val	missense	Exon 1 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.130C>G	p.Leu44Val	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.130C>G	p.Leu44Val	missense	Exon 1 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.130C>G	p.Leu44Val	missense	Exon 1 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.130C>G	p.Leu44Val	missense	Exon 1 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 364 AN: 151760 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00831

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000470 AC: 12 AN: 25538 AF XY: 0.000392

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.000216

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000199

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 284 AN: 1230840 Hom.: 2 Cov.: 31 AF XY: 0.000206 AC XY: 124 AN XY: 601754

African (AFR) AF: 0.00899 AC: 218 AN: 24250

American (AMR) AF: 0.000495 AC: 7 AN: 14130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18054

East Asian (EAS) AF: 0.00 AC: 0 AN: 27022

South Asian (SAS) AF: 0.0000914 AC: 5 AN: 54696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29998

Middle Eastern (MID) AF: 0.00114 AC: 4 AN: 3496

European-Non Finnish (NFE) AF: 0.0000159 AC: 16 AN: 1008648

Other (OTH) AF: 0.000673 AC: 34 AN: 50546

GnomAD4 genome AF: 0.00247 AC: 375 AN: 151868 Hom.: 1 Cov.: 33 AF XY: 0.00259 AC XY: 192 AN XY: 74224

African (AFR) AF: 0.00855 AC: 355 AN: 41522

American (AMR) AF: 0.000917 AC: 14 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67848

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000209 Hom.: 0

Bravo AF: 0.00279

ExAC AF: 0.000401 AC: 5

Asia WGS AF: 0.00204 AC: 7 AN: 3442

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Succinate-semialdehyde dehydrogenase deficiency (2)
-	-	1	ALDH5A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.34
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.053
Sift	Benign	0.18	T
Sift4G	Benign	0.13	T
Polyphen		0.0070	B
Vest4		0.12
MVP		0.56
MPC		0.29
ClinPred		0.012	T
GERP RS		2.9
PromoterAI		-0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.046
gMVP		0.16
Mutation Taster		=95/5	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: rs185042766; hg19: chr6-24495354;