rs373305585

chr9-35091689-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032634.4(PIGO):c.2198G>A(p.Arg733Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,612,562 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R733W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00069 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (26 hom.)
• Consequence: PIGO NM_032634.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.594

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031931996).
• BP6: Variant 9-35091689-C-T is Benign according to our data. Variant chr9-35091689-C-T is described in ClinVar as [Benign]. Clinvar id is 218819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35091689-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00069 (105/152272) while in subpopulation SAS AF= 0.0205 (99/4824). AF 95% confidence interval is 0.0173. There are 5 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGO	NM_032634.4	c.2198G>A	p.Arg733Gln	missense_variant	7/11	ENST00000378617.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGO	ENST00000378617.4	c.2198G>A	p.Arg733Gln	missense_variant	7/11	1	NM_032634.4	P1

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152154 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00231 AC: 568 AN: 245836 Hom.: 10 AF XY: 0.00302 AC XY: 405 AN XY: 134100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0181

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000452

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00117 AC: 1711 AN: 1460290 Hom.: 26 Cov.: 31 AF XY: 0.00167 AC XY: 1216 AN XY: 726500

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0181

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.000690 AC: 105 AN: 152272 Hom.: 5 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00257 AC: 311

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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. -

Hyperphosphatasia with intellectual disability syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	9.9
Dann	Benign	0.92
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.32	N
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.038
Sift	Benign	0.55	T
Sift4G	Benign	0.69	T
Polyphen		0.032	B
Vest4		0.11
MVP		0.30
MPC		0.17
ClinPred		0.0075	T
GERP RS		2.5
Varity_R		0.020
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373305585; hg19: chr9-35091686; COSMIC: COSV53053436; COSMIC: COSV53053436;