rs142658052

Positions:

• chr9-35093180-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6 BP7 BS1

The ENST00000378617.4(PIGO):​c.969T>G​(p.Leu323=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: PIGO ENST00000378617.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.58

Genes affected

PIGO (HGNC:23215): (phosphatidylinositol glycan anchor biosynthesis class O) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid which contains three mannose molecules in its core backbone. The GPI-anchor is found on many blood cells and serves to anchor proteins to the cell surface. This protein is involved in the transfer of ethanolaminephosphate (EtNP) to the third mannose in GPI. At least three alternatively spliced transcripts encoding two distinct isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 9-35093180-A-C is Benign according to our data. Variant chr9-35093180-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 385746.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr9-35093180-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000315 (48/152356) while in subpopulation AFR AF= 0.000866 (36/41580). AF 95% confidence interval is 0.000642. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGO	NM_032634.4	c.969T>G	p.Leu323=	synonymous_variant	6/11	ENST00000378617.4	NP_116023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGO	ENST00000378617.4	c.969T>G	p.Leu323=	synonymous_variant	6/11	1	NM_032634.4	ENSP00000367880	P1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 250878 Hom.: 0 AF XY: 0.0000959 AC XY: 13 AN XY: 135570

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461360 Hom.: 0 Cov.: 33 AF XY: 0.0000812 AC XY: 59 AN XY: 726890

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 27 AN XY: 74506

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000359

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 2 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.9
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs142658052; hg19: chr9-35093177;