rs4646832

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-24495102-G-A
• chr6-24495102-G-C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001080.3(ALDH5A1):​c.106G>A​(p.Gly36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000859 in 1,163,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G36G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00800
• 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: Likely_benign. 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=0.050842613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.106G>A	p.Gly36Arg	missense_variant	Exon 1 of 10	ENST00000357578.8	NP_001071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.106G>A	p.Gly36Arg	missense_variant	Exon 1 of 10	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.59e-7 AC: 1 AN: 1163480 Hom.: 0 Cov.: 31 AF XY: 0.00000178 AC XY: 1 AN XY: 563358

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23452

American (AMR) AF: 0.00 AC: 0 AN: 10412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16138

East Asian (EAS) AF: 0.00 AC: 0 AN: 26662

South Asian (SAS) AF: 0.00 AC: 0 AN: 39042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3204

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 971740

Other (OTH) AF: 0.00 AC: 0 AN: 47090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.1
DANN	Benign	0.79
DEOGEN2	Benign	0.31	T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.49	T;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;.;N
PhyloP100		0.0080
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.030	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.85	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.091
MutPred		0.099		Gain of methylation at G36 (P = 0.0093);Gain of methylation at G36 (P = 0.0093);Gain of methylation at G36 (P = 0.0093);
MVP		0.41
MPC		0.32
ClinPred		0.071	T
GERP RS		-6.6
PromoterAI		0.043	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

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;