rs4646830

Positions:

• chr6-24494822-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The XM_017010753.3(GPLD1):​c.44+145G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 714,560 control chromosomes in the GnomAD database, including 44,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (8971 hom., cov: 32)
  • Exomes 𝑓: 0.35 (35565 hom.)
• Consequence: GPLD1 XM_017010753.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.07

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 6-24494822-C-G is Benign according to our data. Variant chr6-24494822-C-G is described in ClinVar as [Benign]. Clinvar id is 1282291.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPLD1	XM_017010753.3	c.44+145G>C		intron_variant			XP_016866242.1
GPLD1	XM_047418658.1	c.44+145G>C		intron_variant			XP_047274614.1
GPLD1	XR_007059240.1	n.321+145G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPLD1	ENST00000474784.5	n.239+145G>C		intron_variant, non_coding_transcript_variant		5
GPLD1	ENST00000475417.1	n.233+145G>C		intron_variant, non_coding_transcript_variant		3
ALDH5A1	ENST00000491546.5			upstream_gene_variant		5		ENSP00000417687

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51153 AN: 151880 Hom.: 8957 Cov.: 32

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.307

GnomAD4 exome AF: 0.350 AC: 196995 AN: 562562 Hom.: 35565 Cov.: 8 AF XY: 0.349 AC XY: 95606 AN XY: 274040

Gnomad4 AFR exome AF: 0.376

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.200

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.363

Gnomad4 OTH exome AF: 0.334

GnomAD4 genome AF: 0.337 AC: 51217 AN: 151998 Hom.: 8971 Cov.: 32 AF XY: 0.330 AC XY: 24486 AN XY: 74280

Gnomad4 AFR AF: 0.380

Gnomad4 AMR AF: 0.232

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.194

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.332

Gnomad4 NFE AF: 0.352

Gnomad4 OTH AF: 0.310

Alfa AF: 0.352 Hom.: 1169

Bravo AF: 0.332

Asia WGS AF: 0.256 AC: 894 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.7
DANN	Benign	0.57

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4646830; hg19: chr6-24495050;