rs4646828

Variant names:

• chr6-24494696-C-T
• rs4646828
• ENST00000474784.5:n.239+271G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000474784.5(GPLD1):​n.239+271G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,080 control chromosomes in the GnomAD database, including 8,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.30 (8633 hom., cov: 32)
• Consequence: GPLD1 ENST00000474784.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0530
• Publications: 7 publications found

Genes affected

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]

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]

ALDH5A1 Gene-Disease associations (from GenCC):

• succinic semialdehyde dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-24494696-C-T is Benign according to our data. Variant chr6-24494696-C-T is described in ClinVar as Benign. ClinVar VariationId is 1276556.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPLD1	XM_017010753.3	c.44+271G>A		intron_variant	Intron 1 of 25		XP_016866242.1
GPLD1	XM_047418658.1	c.44+271G>A		intron_variant	Intron 1 of 17		XP_047274614.1
GPLD1	XR_007059240.1	n.321+271G>A		intron_variant	Intron 1 of 26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPLD1	ENST00000474784.5	n.239+271G>A		intron_variant	Intron 1 of 10	5
GPLD1	ENST00000475417.1	n.233+271G>A		intron_variant	Intron 1 of 4	3
ALDH5A1	ENST00000491546.5	c.-301C>T		upstream_gene_variant		5		ENSP00000417687.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46339 AN: 151962 Hom.: 8645 Cov.: 32

Gnomad AFR AF: 0.0903

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.328

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.304 AC: 46308 AN: 152080 Hom.: 8633 Cov.: 32 AF XY: 0.302 AC XY: 22449 AN XY: 74308

African (AFR) AF: 0.0899 AC: 3736 AN: 41538

American (AMR) AF: 0.327 AC: 4999 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1637 AN: 3470

East Asian (EAS) AF: 0.289 AC: 1485 AN: 5144

South Asian (SAS) AF: 0.302 AC: 1457 AN: 4822

European-Finnish (FIN) AF: 0.327 AC: 3458 AN: 10572

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28503 AN: 67944

Other (OTH) AF: 0.326 AC: 687 AN: 2108

Alfa AF: 0.382 Hom.: 37247

Bravo AF: 0.296

Asia WGS AF: 0.256 AC: 892 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 15, 2018

GeneDx

Significance: 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	-0.78
CADD	Benign	5.7
DANN	Benign	0.78
PhyloP100		-0.053
PromoterAI		-0.048	Neutral

Splicing

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

Other links and lift over

dbSNP: rs4646828; hg19: chr6-24494924;