rs35287398

chr9-35092483-T-G

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.1404A>C(p.Ala468=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,142 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 33)
  • Exomes 𝑓: 0.015 (216 hom.)
• Consequence: PIGO NM_032634.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.304

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=-0.79).
• BP6: Variant 9-35092483-T-G is Benign according to our data. Variant chr9-35092483-T-G is described in ClinVar as [Benign]. Clinvar id is 262095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.304 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0125 (1910/152296) while in subpopulation SAS AF= 0.0216 (104/4822). AF 95% confidence interval is 0.0182. There are 19 homozygotes in gnomad4. There are 944 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGO	NM_032634.4	c.1404A>C	p.Ala468=	synonymous_variant	7/11	ENST00000378617.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGO	ENST00000378617.4	c.1404A>C	p.Ala468=	synonymous_variant	7/11	1	NM_032634.4	P1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1903 AN: 152178 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0145 AC: 3625 AN: 250786 Hom.: 48 AF XY: 0.0154 AC XY: 2092 AN XY: 135532

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.00876

Gnomad ASJ exome AF: 0.0321

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0224

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0145 AC: 21214 AN: 1461846 Hom.: 216 Cov.: 33 AF XY: 0.0153 AC XY: 11094 AN XY: 727214

Gnomad4 AFR exome AF: 0.00633

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0335

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0247

Gnomad4 FIN exome AF: 0.0155

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome AF: 0.0125 AC: 1910 AN: 152296 Hom.: 19 Cov.: 33 AF XY: 0.0127 AC XY: 944 AN XY: 74464

Gnomad4 AFR AF: 0.00575

Gnomad4 AMR AF: 0.00941

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0216

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0155

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0153 Hom.: 10

Bravo AF: 0.0114

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0204

EpiControl AF: 0.0196

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hyperphosphatasia with intellectual disability syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.5
Dann	Benign	0.67

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: rs35287398; hg19: chr9-35092480; COSMIC: COSV53054552; COSMIC: COSV53054552;