rs2298314

Variant names:

• chr9-35089406-G-A
• rs2298314
• NM_032634.4:c.3114C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_032634.4(PIGO):​c.3114C>T​(p.Leu1038Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 1,614,158 control chromosomes in the GnomAD database, including 2,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (260 hom., cov: 33)
  • Exomes 𝑓: 0.028 (2109 hom.)
• Consequence: PIGO NM_032634.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.51
• Publications: 9 publications found

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]

PIGO Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hyperphosphatasia with intellectual disability syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 9-35089406-G-A is Benign according to our data. Variant chr9-35089406-G-A is described in ClinVar as Benign. ClinVar VariationId is 262097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGO	NM_032634.4	c.3114C>T	p.Leu1038Leu	synonymous_variant	Exon 10 of 11	ENST00000378617.4	NP_116023.2
PIGO	NM_001201484.2	c.1863C>T	p.Leu621Leu	synonymous_variant	Exon 12 of 13		NP_001188413.1
PIGO	NM_152850.4	c.1863C>T	p.Leu621Leu	synonymous_variant	Exon 11 of 12		NP_690577.2
PIGO	XM_005251619.4	c.3114C>T	p.Leu1038Leu	synonymous_variant	Exon 10 of 11		XP_005251676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGO	ENST00000378617.4	c.3114C>T	p.Leu1038Leu	synonymous_variant	Exon 10 of 11	1	NM_032634.4	ENSP00000367880.3

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 4794 AN: 152172 Hom.: 262 Cov.: 33

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.0646

Gnomad FIN AF: 0.0448

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0310

GnomAD2 exomes AF: 0.0469 AC: 11787 AN: 251430 AF XY: 0.0461

Gnomad AFR exome AF: 0.0162

Gnomad AMR exome AF: 0.0149

Gnomad ASJ exome AF: 0.0505

Gnomad EAS exome AF: 0.301

Gnomad FIN exome AF: 0.0489

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0350

GnomAD4 exome AF: 0.0276 AC: 40319 AN: 1461868 Hom.: 2109 Cov.: 33 AF XY: 0.0288 AC XY: 20921 AN XY: 727238

African (AFR) AF: 0.0171 AC: 573 AN: 33480

American (AMR) AF: 0.0158 AC: 708 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 1379 AN: 26136

East Asian (EAS) AF: 0.276 AC: 10941 AN: 39698

South Asian (SAS) AF: 0.0570 AC: 4914 AN: 86252

European-Finnish (FIN) AF: 0.0456 AC: 2438 AN: 53416

Middle Eastern (MID) AF: 0.0484 AC: 279 AN: 5768

European-Non Finnish (NFE) AF: 0.0149 AC: 16611 AN: 1112002

Other (OTH) AF: 0.0410 AC: 2476 AN: 60394

GnomAD4 genome AF: 0.0314 AC: 4786 AN: 152290 Hom.: 260 Cov.: 33 AF XY: 0.0347 AC XY: 2585 AN XY: 74458

African (AFR) AF: 0.0177 AC: 736 AN: 41572

American (AMR) AF: 0.0224 AC: 342 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3470

East Asian (EAS) AF: 0.279 AC: 1444 AN: 5168

South Asian (SAS) AF: 0.0649 AC: 313 AN: 4824

European-Finnish (FIN) AF: 0.0448 AC: 476 AN: 10620

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0179 AC: 1217 AN: 68034

Other (OTH) AF: 0.0302 AC: 64 AN: 2116

Alfa AF: 0.0202 Hom.: 58

Bravo AF: 0.0299

Asia WGS AF: 0.156 AC: 542 AN: 3478

EpiCase AF: 0.0220

EpiControl AF: 0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperphosphatasia with intellectual disability syndrome 2 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	6.9
DANN	Benign	0.70
PhyloP100		3.5
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2298314; hg19: chr9-35089403; COSMIC: COSV53052503; COSMIC: COSV53052503;