chr6-24495102-G-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

Selected	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
	ALDH5A1	NM_170740.1		c.106G>C	p.Gly36Arg	missense	Exon 1 of 11	NP_733936.1
	ALDH5A1	NM_001368954.1		c.106G>C	p.Gly36Arg	missense	Exon 1 of 9	NP_001355883.1

Ensembl Transcripts

Selected	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
	ALDH5A1	ENST00000348925.2	TSL:1	c.106G>C	p.Gly36Arg	missense	Exon 1 of 11	ENSP00000314649.3
	ALDH5A1	ENST00000491546.5	TSL:5	c.106G>C	p.Gly36Arg	missense	Exon 1 of 9	ENSP00000417687.1

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jan 29, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALDH5A1-related disorder Benign:1

Jan 07, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:1

Jul 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19164088, 27056292)

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;