rs76932500

Positions:

• chr9-35092414-C-G
• chr9-35092414-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032634.4(PIGO):​c.1473G>C​(p.Leu491=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00652 in 1,614,258 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (45 hom.)
• Consequence: PIGO NM_032634.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.569

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 9-35092414-C-G is Benign according to our data. Variant chr9-35092414-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 382941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.569 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00546 (832/152368) while in subpopulation NFE AF= 0.00773 (526/68026). AF 95% confidence interval is 0.00719. There are 5 homozygotes in gnomad4. There are 424 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGO	NM_032634.4	c.1473G>C	p.Leu491=	synonymous_variant	7/11	ENST00000378617.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGO	ENST00000378617.4	c.1473G>C	p.Leu491=	synonymous_variant	7/11	1	NM_032634.4	P1

Frequencies

GnomAD3 genomes AF: 0.00546 AC: 832 AN: 152250 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00773

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00510 AC: 1282 AN: 251128 Hom.: 6 AF XY: 0.00504 AC XY: 684 AN XY: 135736

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.00746

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00663 AC: 9697 AN: 1461890 Hom.: 45 Cov.: 32 AF XY: 0.00636 AC XY: 4623 AN XY: 727246

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00131

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.00755

Gnomad4 OTH exome AF: 0.00594

GnomAD4 genome AF: 0.00546 AC: 832 AN: 152368 Hom.: 5 Cov.: 33 AF XY: 0.00569 AC XY: 424 AN XY: 74508

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.00773

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00650 Hom.: 2

Bravo AF: 0.00416

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00605

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PIGO: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 23, 2018	- -

Hyperphosphatasia with intellectual disability syndrome 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PIGO-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.19
DANN	Benign	0.41
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: rs76932500; hg19: chr9-35092411;