6-24494822-C-A

Variant names:

• chr6-24494822-C-A
• rs4646830
• ENST00000859835.1:c.-175C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000859835.1(ALDH5A1):​c.-175C>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 0.00000177 in 564,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: ALDH5A1 ENST00000859835.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).

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.-175C>A		upstream_gene	N/A	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.-175C>A		upstream_gene	N/A	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.-175C>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.-175C>A		5_prime_UTR	Exon 1 of 10	ENSP00000529894.1
	ALDH5A1	ENST00000859836.1		c.-175C>A		5_prime_UTR	Exon 1 of 9	ENSP00000529895.1
	GPLD1	ENST00000474784.5	TSL:5	n.239+145G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000177 AC: 1 AN: 564168 Hom.: 0 Cov.: 8 AF XY: 0.00000364 AC XY: 1 AN XY: 274806

⚠️ 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: 12486

American (AMR) AF: 0.00 AC: 0 AN: 7108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10256

East Asian (EAS) AF: 0.00 AC: 0 AN: 22700

South Asian (SAS) AF: 0.00 AC: 0 AN: 8826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1852

European-Non Finnish (NFE) AF: 0.00000220 AC: 1 AN: 454504

Other (OTH) AF: 0.00 AC: 0 AN: 26070

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.6
DANN	Benign	0.84
PhyloP100		-1.1
PromoterAI		-0.055	Neutral

Splicing

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

Other links and lift over

dbSNP: rs4646830; hg19: chr6-24495050;