PIGB

protein-coding

phosphatidylinositol glycan anchor biosynthesis class B, the group of Dolichyl D-mannosyl phosphate dependent mannosyltransferases|Phosphatidylinositol glycan anchor biosynthesis

Gene summary

This gene encodes a transmembrane protein that is located in the endoplasmic reticulum and is involved in GPI-anchor biosynthesis. The glycosylphosphatidylinositol (GPI) anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene is thought to encode a member of a family of dolichol-phosphate-mannose (Dol-P-Man) dependent mannosyltransferases. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004855.5

Inheritance

ClinVar variants

P:33U:161B:111

Top phenotype

Developmental and epileptic encephalopathy 80

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr15:55,318,960-55,355,648

External References & Databases

Ensembl (ENSG00000069943)

Transcript & Mutation Effects

hg38 • Region Span ~36.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 80MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032822

Submitter: ClinGen

*PIGB* was first reported in related to DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 80 (MONDO:0032822) in 1996 (Takahashi et al., 1996, PMID:8861954). DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 80 is an autosomal recessive neurologic disorder characterized by the onset of refractory seizures in the first year of life. Patients have severe global developmental delay and may have additional variable features, including dysmorphic or coarse facial features, distal skeletal abnormalities, and impaired hearing or vision. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI) and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Murakami et al., 2019). The *PIGB* gene encodes a transmembrane protein that is located in the endoplasmic reticulum and is involved in GPI-anchor biosynthesis. The GPI anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene is thought to encode a member of a family of dolichol-phosphate-mannose (Dol-P-Man) dependent mannosyltransferases. [provided by RefSeq, Jul 2008]. More than 350 unique variants (e.g., frameshift, missense, in-frame indel, nonsense and splice sites) have been reported in humans by ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Ten variants that have been reported in 8 probands in 1 publication (Murakami et al., 2019; PMID: 31256876), are included in this curation. A model system that describes restored function of the GPI anchor synthesis pathway in a mutant mouse cell line (Takahashi et al., 1996, PMID:8861954) also supports this gene-disease relationship. In summary, there is moderate evidence to support *PIGB* in association with DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 80. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on meeting date December 5, 2024 (SOP Version 10).

developmental and epileptic encephalopathy, 80STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032822

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 80STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032822

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 80MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032822

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 80DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032822

Submitter: G2P

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 80AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 31256876

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGB variants in ClinVar

8 Conditions Cataloged

not providedTotal: 354

Inborn genetic diseasesTotal: 67

Developmental and epileptic encephalopathy, 80Total: 22

not specifiedTotal: 18

PIGB-related disorderTotal: 7

Hyperphosphatasia with intellectual disability syndrome 1Total: 1

Acrofrontofacionasal dysostosis 1Total: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004855.5. 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			3 clinvar	99 clinvar		102
missense	2 clinvar	4 clinvar	150 clinvar	8 clinvar	4 clinvar	168
nonsense	12 clinvar	2 clinvar	1 clinvar			15
start loss						0
frameshift	6 clinvar	1 clinvar	3 clinvar			10
splice donor/acceptor (+/-2bp)		6 clinvar	4 clinvar			10
Total	20	13	161	107	4	305

Highest pathogenic variant AF is 0.000135318

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004855.5	RefSeq	NP_004846.4	12	MANE Select
ENST00000164305.10	Ensembl	ENSP00000164305.5	12	MANE Select
ENST00000539642.5	Ensembl	ENSP00000438963.2	12	Standard
ENST00000565367.5	Ensembl	ENSP00000455943.1	3	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
mannosylation

Molecular Function

mannosyltransferase activity
glycolipid mannosyltransferase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000164305
Coding exons: 12
Length: 36689
Individuals with no LoFs: 124611
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 124653
p: 0.000168

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.595	239	266	0.897	0.0000126	3617
Missense (PolyPhen)		71	91.54	0.77562		1246
Synonymous	0.295	88	91.6	0.961	0.00000420	1015
Loss of Function	1.30	20	27.3	0.732	0.00000135	364

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00045	0.00045	rare
Latino/Admixed American	0.00019	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00040	0.00039	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00016	0.00015	rare
South Asian	0.000099	0.000098	rare
Other	0.00018	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the third alpha-1,2-mannose to Man2-GlcN-acyl-PI during GPI precursor assembly. {ECO:0000269|PubMed:8861954}.;

Recessive Scores

pRec: 0.0985

Essentials

Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.302

Gene Damage Prediction

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