PIGG

protein-coding

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

Gene summary

This gene encodes an enzyme involved in glycosylphosphatidylinositol-anchor biosynthesis. The encoded protein, which is localized to the endoplasmic reticulum, is involved in transferring ethanoloamine phosphate to mannose 2 of glycosylphosphatidylinositol species H7 to form species H8. Allelic variants of this gene have been associated with intellectual disability, hypotonia, and early-onset seizures. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

MANE transcript

NM_001127178.3

Inheritance

AR, BG

ClinVar variants

P:103U:484B:334

Top phenotype

Blood group, EMM system; Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr4:499,210-540,200

External References & Databases

Ensembl (ENSG00000174227)

Transcript & Mutation Effects

hg38 • Region Span ~41.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disability, autosomal recessive 53STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014832

Submitter: PanelApp Australia

intellectual disability, autosomal recessive 53STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014832

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disability, autosomal recessive 53STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014832

Submitter: G2P

intellectual disability, autosomal recessive 53DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014832

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Blood group, EMM system; Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophyBG/AR

Manifestation: Hematologic; Neurologic

Intervention: Hematologic

Rationale: Variants associated with a blood group may be important in specific situations (eg, related to transfusion)

Refs: 26996948; 33763700; 34535746

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGG variants in ClinVar

10 Conditions Cataloged

Intellectual disability, autosomal recessive 53Total: 943

not providedTotal: 242

Inborn genetic diseasesTotal: 165

not specifiedTotal: 79

PIGG-related disorderTotal: 43

Emm-null phenotypeTotal: 6

BLOOD GROUP, EMM SYSTEMTotal: 5

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001127178.3. 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			6 clinvar	294 clinvar		300
missense	1 clinvar	7 clinvar	469 clinvar	38 clinvar	2 clinvar	517
nonsense	16 clinvar	10 clinvar	4 clinvar			30
start loss		1 clinvar				1
frameshift	28 clinvar	20 clinvar	2 clinvar			50
splice donor/acceptor (+/-2bp)	6 clinvar	14 clinvar	3 clinvar			23
Total	51	52	484	332	2	921

Highest pathogenic variant AF is 0.0010649185

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 117 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001127178.3	RefSeq	NP_001120650.1	13	MANE Select
ENST00000453061.7	Ensembl	ENSP00000415203.2	13	MANE Select
NM_001289051.2	RefSeq	NP_001275980.1	12	Standard
NM_001289052.2	RefSeq	NP_001275981.1	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
preassembly of GPI anchor in ER membrane

Molecular Function

phosphotransferase activity, for other substituted phosphate groups
CP2 mannose-ethanolamine phosphotransferase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
membrane
integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000453061
Coding exons: 13
Length: 40997
Individuals with no LoFs: 125458
Homozygous LoFs: 0
Heterozygous LoFs: 290
Defined: 125748
p: 0.00115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.168	574	563	1.02	0.0000325	6303
Missense (PolyPhen)		191	205.27	0.9305		2457
Synonymous	-0.600	266	254	1.05	0.0000176	2090
Loss of Function	1.61	28	38.9	0.720	0.00000189	470

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00078	0.00078	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.0018	0.0018	notable
South Asian	0.0012	0.0012	notable
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ethanolamine phosphate transferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers ethanolamine phosphate to the GPI second mannose. {ECO:0000269|PubMed:15632136}.;
Disease: DISEASE: Mental retardation, autosomal recessive 53 (MRT53) [MIM:616917]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Most MRT53 patients manifest severely delayed psychomotor development, hypotonia, and early-onset seizures. Additional features, such as cerebellar hypoplasia and ataxia have been observed in some patients. Note=The disease is caused by mutations affecting the gene represented in this entry. Cells from patients carrying PIGG disease-causing mutations show abnormal accumulation of the GPI precursors H7 and H7' and absence of mature GPI precursor H8, consistent with a loss of function. However, GPI-anchored proteins, including CD59, CD55, CD24 and CD16, are normally expressed at the cell surface of lymphocytes and granulocytes and CD59 exhibits sensitivity to bacterial phosphatidylinositol- specific phospholipase C, suggesting a normal structure. The role of PIGG in MRT53 etiology is not clear. {ECO:0000269|PubMed:26996948}.;

Recessive Scores

pRec: 0.122

Intolerance Scores

LoFtool: 0.852
RVIS EVS: 1.79
RVIS percentile EVS: 96.87

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.397

Gene Damage Prediction

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