rs4646828

Variant names:

• chr6-24494696-C-T
• rs4646828
• XM_017010753.3:c.44+271G>A

Variant summary

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

The ENST00000475417.1(GPLD1):​n.233+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 ENST00000475417.1 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000475417.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPLD1	ENST00000474784.5	TSL:5	n.239+271G>A		intron	N/A
	GPLD1	ENST00000475417.1	TSL:3	n.233+271G>A		intron	N/A
	ALDH5A1	ENST00000859838.1		c.-301C>T		upstream_gene	N/A	ENSP00000529897.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4646828;

hg19: chr6-24494924;