PIGP
protein-codingphosphatidylinositol glycan anchor biosynthesis class P, the group of Glycosylphosphatidylinositol-N-acetylglucosaminyltransferase complex|Phosphatidylinositol glycan anchor biosynthesis
Gene summary
This gene encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells that serves to anchor proteins to the cell surface. The encoded protein is a component of the GPI-N-acetylglucosaminyltransferase complex that catalyzes the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). This gene is located in the Down Syndrome critical region on chromosome 21 and is a candidate for the pathogenesis of Down syndrome. This gene has multiple pseudogenes and is a member of the phosphatidylinositol glycan anchor biosynthesis gene family. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Feb 2016]
- DSCR5
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0100247
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0033364
Submitter: ClinGen
*PIGP* was first reported in relation to “developmental and epileptic encephalopathy, 55” an autosomal recessive condition, in 2017 (Johnstone et al, PMID: 28334793). This is the only condition associated with PIGP in OMIM. Four variants (one C-terminal frameshift, one missense, one initiator codon, and one multi-gene deletion) that have been reported in 5 probands in 5 publications (Johnstone et al, 2017, PMID: 28334793; Krenn et al, 2019, PMID: 31139695; Vetro et al, 2020, PMID: 32042915; Kahn et al, 2022, PMID: 36002593; Martín-Grau et al, 2023, PMID: 37125481) are included in this curation. Two of the variants, c.2C>T and c.384del, have been reported in more than one unrelated individual. (Total score for genetic evidence = points). The mechanism of pathogenicity appears to be loss of function based on reduction of surface localization of GPI-anchored proteins in granulocytes from affected individuals, and in invitro functional studies. This gene-disease relationship is also supported by the biochemical function of the gene product, and interaction with the products of other genes which have been associated with the same condition. PIGP is part of a multi-subunit complex involved in the first step of synthesis of the GPI anchor (Watanabe et al, 2000, PMID: 10944123). In that complex, it interacts with various proteins including PIGA, which has been definitively associated with “complex neurological disorder” by the Epilepsy Gene Curation Expert Panel (Watanabe et al, 2000, PMID: 10944123). (Score for experimental evidence = ) In summary, there is moderate evidence supporting the relationship between PIGP and the autosomal recessive disorder “developmental and epileptic encephalopathy, 55”. This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on December 5, 2024 (SOP version #11).
Inheritance Pattern: AR
Disease ID:MONDO:0033364
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0100062
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0033364
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0033364
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Neurologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PIGP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_153682.3. 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 | 1 | 28 | 1 | 30 | ||
| missense | 52 | 1 | 4 | 57 | ||
| nonsense | 5 | 5 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 3 | 5 | |||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 3 | 65 | 29 | 5 | 102 |
Highest pathogenic variant AF is 0.00007372813
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_710149.1 | 4 | MANE Select | |
| Ensembl | ENSP00000353719.3 | 4 | MANE Select | |
| RefSeq | NP_001307409.1 | 4 | Standard | |
| RefSeq | NP_057514.2 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pigp | Danio rerio | Structure: caudal fin Quality: folded abnormal |
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
- phosphatidylinositol N-acetylglucosaminyltransferase activity
Cellular Component
- glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex
- endoplasmic reticulum membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000464265
- Coding exons
- 4
- Length
- 14001
- Individuals with no LoFs
- 125697
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 51
- Defined
- 125748
- p
- 0.000203
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.558 | 92 | 78.1 | 1.18 | 0.00000349 | 1018 |
| Missense (PolyPhen) | 10 | 16.714 | 0.59829 | 241 | ||
| Synonymous | -1.03 | 38 | 30.7 | 1.24 | 0.00000150 | 298 |
| Loss of Function | 0.882 | 5 | 7.63 | 0.655 | 3.22e-7 | 98 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.00060 | 0.00060 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0.00046 | 0.00046 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Part of the complex catalyzing the transfer of N- acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol, the first step of GPI biosynthesis. {ECO:0000269|PubMed:10944123, ECO:0000269|PubMed:28334793}.;
Recessive Scores
- pRec
- 0.124
Intolerance Scores
- LoFtool
- 0.941
- RVIS EVS
- 0.55
- RVIS percentile EVS
- 81.38
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.671
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |