rs4646831

chr6-24494823-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The XM_017010753.3(GPLD1):c.44+144C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 735,668 control chromosomes in the GnomAD database, including 522 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 0.029 (107 hom., cov: 33)
  • Exomes 𝑓: 0.028 (415 hom.)
• Consequence: GPLD1 XM_017010753.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPLD1	XM_017010753.3	c.44+144C>T		intron_variant
GPLD1	XM_047418658.1	c.44+144C>T		intron_variant
GPLD1	XR_007059240.1	n.321+144C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPLD1	ENST00000474784.5	n.239+144C>T		intron_variant, non_coding_transcript_variant		5
GPLD1	ENST00000475417.1	n.233+144C>T		intron_variant, non_coding_transcript_variant		3
ALDH5A1	ENST00000491546.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4365 AN: 152136 Hom.: 106 Cov.: 33

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.0833

Gnomad SAS AF: 0.0987

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0306

GnomAD4 exome AF: 0.0284 AC: 16563 AN: 583414 Hom.: 415 Cov.: 8 AF XY: 0.0284 AC XY: 8068 AN XY: 283652

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.0273

Gnomad4 ASJ exome AF: 0.0277

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.0223

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0356

GnomAD4 genome AF: 0.0287 AC: 4375 AN: 152254 Hom.: 107 Cov.: 33 AF XY: 0.0291 AC XY: 2169 AN XY: 74442

Gnomad4 AFR AF: 0.0219

Gnomad4 AMR AF: 0.0276

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.0837

Gnomad4 SAS AF: 0.0980

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.0250

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0277 Hom.: 8

Bravo AF: 0.0287

Asia WGS AF: 0.107 AC: 372 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	5.9
Dann	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4646831; hg19: chr6-24495051;