PIGO

protein-coding

phosphatidylinositol glycan anchor biosynthesis class O, the group of Phosphatidylinositol glycan anchor biosynthesis

Gene summary

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]

MANE transcript

NM_032634.4

Inheritance

ClinVar variants

P:92U:534B:318

Top phenotype

Hyperphosphatasia with impaired intellectual development syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr9:35,085,493-35,096,619

External References & Databases

Ensembl (ENSG00000165282)

Transcript & Mutation Effects

hg38 • Region Span ~11.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperphosphatasia with impaired intellectual development syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013882

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

PIGO was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2012 (Krawitz et al., PMID: 22683086). At least 15 variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data (12 points). Variants in this gene have been reported in at least 7 probands in 4 publications (PMID: 24417746, 27177984, 22683086, 28337824). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is recessive loss of function (Krawitz et al., PMID: 22683086). Of note, hyperphosphatasia is not a defining feature of this condition, but rather a biochemical phenotype that is occasionally detected in affected individuals. In summary, PIGO is definitively associated with an autosomal recessive complex neurodevelopmental disorder . This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Working Group on 07/20/21 (SOP Version 8).

hyperphosphatasia with impaired intellectual development syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013882

Submitter: G2P

hyperphosphatasia-intellectual disability syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016596

Submitter: Orphanet

hyperphosphatasia with impaired intellectual development syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013882

Submitter: PanelApp Australia

hyperphosphatasia with impaired intellectual development syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013882

Submitter: Illumina

Clinical Genomic Database (CGD)

Hyperphosphatasia with impaired intellectual development syndrome 2AR

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 22683086

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGO variants in ClinVar

10 Conditions Cataloged

Hyperphosphatasia with intellectual disability syndrome 2Total: 910

not providedTotal: 220

Inborn genetic diseasesTotal: 141

not specifiedTotal: 71

PIGO-related disorderTotal: 28

Hyperphosphatasia-intellectual disability syndromeTotal: 3

Hyperphosphatasia with intellectual disability syndrome 1Total: 1

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032634.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			12 clinvar	286 clinvar	3 clinvar	301
missense	1 clinvar	10 clinvar	515 clinvar	27 clinvar	2 clinvar	555
nonsense	19 clinvar	7 clinvar	2 clinvar			28
start loss						0
frameshift	34 clinvar	13 clinvar	3 clinvar			50
splice donor/acceptor (+/-2bp)	1 clinvar	7 clinvar	2 clinvar			10
Total	55	37	534	313	5	944

Highest pathogenic variant AF is 0.001520275

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032634.4	RefSeq	NP_116023.2	10	MANE Select
ENST00000378617.4	Ensembl	ENSP00000367880.3	10	MANE Select
NM_001201484.2	RefSeq	NP_001188413.1	11	Standard
NM_152850.4	RefSeq	NP_690577.2	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycosylphosphatidylinositol (GPI)-anchor biosynthesis - Homo sapiens (human)
Synthesis of glycosylphosphatidylinositol (GPI)
Post-translational modification: synthesis of GPI-anchored proteins
Post-translational protein modification
Metabolism of proteins

Biological Process

GPI anchor biosynthetic process

Molecular Function

mannose-ethanolamine phosphotransferase activity

Cellular Component

endoplasmic reticulum membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378617
Coding exons: 10
Length: 7907
Individuals with no LoFs: 125620
Homozygous LoFs: 0
Heterozygous LoFs: 128
Defined: 125748
p: 0.000509

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.957	549	616	0.892	0.0000343	6925
Missense (PolyPhen)		154	192.89	0.79838		2338
Synonymous	-0.943	275	256	1.07	0.0000137	2454
Loss of Function	2.50	23	40.1	0.573	0.00000222	406

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00056	0.00055	rare
Latino/Admixed American	0.00051	0.00049	rare
Ashkenazi Jewish	0.00020	0.000099	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00075	0.00075	rare
South Asian	0.00013	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ethanolamine phosphate transferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers ethanolamine phosphate to the GPI third mannose which links the GPI-anchor to the C-terminus of the proteins by an amide bond. {ECO:0000269|PubMed:24049131, ECO:0000269|PubMed:28337824}.;
Disease: DISEASE: Hyperphosphatasia with mental retardation syndrome 2 (HPMRS2) [MIM:614749]: An autosomal recessive form of intellectual disability characterized by facial dysmorphism, brachytelephalangy, and persistent elevated serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures. {ECO:0000269|PubMed:22683086, ECO:0000269|PubMed:24049131, ECO:0000269|PubMed:28337824, ECO:0000269|PubMed:28545593}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0915

Intolerance Scores

LoFtool: 0.653
RVIS EVS: -1.35
RVIS percentile EVS: 4.61

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.416

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium