6-24494888-C-T

Variant names:

• chr6-24494888-C-T
• rs544626175
• ENST00000491546.5:c.-109C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000491546.5(ALDH5A1):​c.-109C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,174,042 control chromosomes in the GnomAD database, including 15 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 0.0074 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (4 hom.)
• Consequence: ALDH5A1 ENST00000491546.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0850
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00737 (1122/152304) while in subpopulation AFR AF = 0.0253 (1052/41572). AF 95% confidence interval is 0.024. There are 11 homozygotes in GnomAd4. There are 542 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.-109C>T		upstream_gene_variant		ENST00000357578.8	NP_001071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.-109C>T		upstream_gene_variant		1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1123 AN: 152188 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.000686 AC: 701 AN: 1021738 Hom.: 4 Cov.: 16 AF XY: 0.000618 AC XY: 300 AN XY: 485198

African (AFR) AF: 0.0225 AC: 477 AN: 21234

American (AMR) AF: 0.00280 AC: 22 AN: 7864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13136

East Asian (EAS) AF: 0.00 AC: 0 AN: 24956

South Asian (SAS) AF: 0.00 AC: 0 AN: 19540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21138

Middle Eastern (MID) AF: 0.000732 AC: 2 AN: 2732

European-Non Finnish (NFE) AF: 0.000170 AC: 148 AN: 870218

Other (OTH) AF: 0.00127 AC: 52 AN: 40920

GnomAD4 genome AF: 0.00737 AC: 1122 AN: 152304 Hom.: 11 Cov.: 33 AF XY: 0.00728 AC XY: 542 AN XY: 74476

African (AFR) AF: 0.0253 AC: 1052 AN: 41572

American (AMR) AF: 0.00340 AC: 52 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68010

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00698 Hom.: 2

Bravo AF: 0.00808

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 16, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.1
DANN	Benign	0.88
PhyloP100		0.085
PromoterAI		-0.15	Neutral
Mutation Taster		=299/1	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: rs544626175; hg19: chr6-24495116;