rs4646831

Variant names:

• chr6-24494823-G-A
• rs4646831
• ENST00000859835.1:c.-174G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-24494823-G-A
• chr6-24494823-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000859835.1(ALDH5A1):​c.-174G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 735,668 control chromosomes in the GnomAD database, including 522 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.029 (107 hom., cov: 33)
  • Exomes 𝑓: 0.028 (415 hom.)
• Consequence: ALDH5A1 ENST00000859835.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000859835.1. 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.-174G>A		upstream_gene	N/A	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.-174G>A		upstream_gene	N/A	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.-174G>A		upstream_gene	N/A	NP_001355883.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000859835.1		c.-174G>A		5_prime_UTR	Exon 1 of 10	ENSP00000529894.1
	ALDH5A1	ENST00000859836.1		c.-174G>A		5_prime_UTR	Exon 1 of 9	ENSP00000529895.1
	GPLD1	ENST00000474784.5	TSL:5	n.239+144C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4365 AN: 152136 Hom.: 106 Cov.: 33

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.0833

Gnomad SAS AF: 0.0987

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0306

GnomAD4 exome AF: 0.0284 AC: 16563 AN: 583414 Hom.: 415 Cov.: 8 AF XY: 0.0284 AC XY: 8068 AN XY: 283652

African (AFR) AF: 0.0253 AC: 325 AN: 12852

American (AMR) AF: 0.0273 AC: 194 AN: 7110

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 287 AN: 10356

East Asian (EAS) AF: 0.106 AC: 2417 AN: 22734

South Asian (SAS) AF: 0.105 AC: 957 AN: 9078

European-Finnish (FIN) AF: 0.0223 AC: 454 AN: 20396

Middle Eastern (MID) AF: 0.0549 AC: 104 AN: 1894

European-Non Finnish (NFE) AF: 0.0230 AC: 10877 AN: 472368

Other (OTH) AF: 0.0356 AC: 948 AN: 26626

GnomAD4 genome AF: 0.0287 AC: 4375 AN: 152254 Hom.: 107 Cov.: 33 AF XY: 0.0291 AC XY: 2169 AN XY: 74442

African (AFR) AF: 0.0219 AC: 909 AN: 41574

American (AMR) AF: 0.0276 AC: 423 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3470

East Asian (EAS) AF: 0.0837 AC: 432 AN: 5162

South Asian (SAS) AF: 0.0980 AC: 472 AN: 4818

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10612

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0250 AC: 1703 AN: 67994

Other (OTH) AF: 0.0360 AC: 76 AN: 2112

Alfa AF: 0.0273 Hom.: 8

Bravo AF: 0.0287

Asia WGS AF: 0.107 AC: 372 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.9
DANN	Benign	0.89
PhyloP100		-0.39
PromoterAI		0.019	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4646831; hg19: chr6-24495051;