NM_001080.3:c.106G>C

Variant names:

• chr6-24495102-G-C
• rs4646832
• NM_001080.3:c.106G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001080.3(ALDH5A1):​c.106G>C​(p.Gly36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,315,212 control chromosomes in the GnomAD database, including 855 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G36G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (104 hom., cov: 33)
  • Exomes 𝑓: 0.028 (751 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00800
• Publications: 11 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=0.0016960204).
• BP6: Variant 6-24495102-G-C is Benign according to our data. Variant chr6-24495102-G-C is described in ClinVar as Benign. ClinVar VariationId is 285783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.091 is higher than 0.05.

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.106G>C	p.Gly36Arg	missense	Exon 1 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.106G>C	p.Gly36Arg	missense	Exon 1 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.106G>C	p.Gly36Arg	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.106G>C	p.Gly36Arg	missense	Exon 1 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.106G>C	p.Gly36Arg	missense	Exon 1 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.106G>C	p.Gly36Arg	missense	Exon 1 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4184 AN: 151744 Hom.: 103 Cov.: 33

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.0827

Gnomad SAS AF: 0.0991

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0260

GnomAD2 exomes AF: 0.0407 AC: 500 AN: 12294 AF XY: 0.0450

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.0236

Gnomad ASJ exome AF: 0.0321

Gnomad EAS exome AF: 0.0616

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0220

Gnomad OTH exome AF: 0.0505

GnomAD4 exome AF: 0.0280 AC: 32598 AN: 1163360 Hom.: 751 Cov.: 31 AF XY: 0.0288 AC XY: 16250 AN XY: 563270

African (AFR) AF: 0.0218 AC: 511 AN: 23452

American (AMR) AF: 0.0220 AC: 229 AN: 10410

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 447 AN: 16134

East Asian (EAS) AF: 0.104 AC: 2780 AN: 26662

South Asian (SAS) AF: 0.0941 AC: 3667 AN: 38982

European-Finnish (FIN) AF: 0.0222 AC: 570 AN: 25732

Middle Eastern (MID) AF: 0.0553 AC: 177 AN: 3202

European-Non Finnish (NFE) AF: 0.0233 AC: 22607 AN: 971700

Other (OTH) AF: 0.0342 AC: 1610 AN: 47086

GnomAD4 genome AF: 0.0276 AC: 4192 AN: 151852 Hom.: 104 Cov.: 33 AF XY: 0.0283 AC XY: 2098 AN XY: 74212

African (AFR) AF: 0.0194 AC: 807 AN: 41514

American (AMR) AF: 0.0218 AC: 332 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3470

East Asian (EAS) AF: 0.0832 AC: 426 AN: 5122

South Asian (SAS) AF: 0.0983 AC: 475 AN: 4830

European-Finnish (FIN) AF: 0.0165 AC: 173 AN: 10488

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0254 AC: 1726 AN: 67864

Other (OTH) AF: 0.0314 AC: 66 AN: 2102

Alfa AF: 0.0272 Hom.: 8

Bravo AF: 0.0264

ExAC AF: 0.0287 AC: 836

Asia WGS AF: 0.106 AC: 365 AN: 3444

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.3
DANN	Benign	0.62
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.0080
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.10
Sift	Benign	0.85	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.091
MutPred		0.099		Gain of methylation at G36 (P = 0.0093)
MPC		0.32
ClinPred		0.0043	T
GERP RS		-6.6
PromoterAI		-0.065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.045
gMVP		0.38
Mutation Taster		=99/1	polymorphism (auto)

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: rs4646832; hg19: chr6-24495330; COSMIC: COSV62373880;