PIGF
protein-codingphosphatidylinositol glycan anchor biosynthesis class F, the group of Phosphatidylinositol glycan anchor biosynthesis
Gene summary
This gene encodes a protein involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor, a glycolipid containing three mannose molecules in its core backbone, is found on many blood cells where it serves to anchor proteins to the cell surface. The encoded protein and another GPI synthesis protein, PIGO, function in the transfer of ethanolaminephosphate to the third mannose in GPI. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~36.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015286
Submitter: ClinGen
*PIGF* was first reported in relation to autosomal recessive congenital disorder of glycosylation (also known as onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (OORS)) in 2021 (Salian et al, PMID: 33386993). In this report, the same biallelic missense variant was identified by exome sequencing in two unrelated probands from the same geographical region of India (Salian et al, 2021, PMID: 33386993). The mechanism of pathogenicity appears to be loss of function, although data is limited. This gene-disease relationship is also supported by experimental evidence, including the biochemical function of *PIGF*. *PIGF* appears to stabilize two different enzymes, *PIGG* and *PIGO*, which are responsible for the transfer of phoshoethanolamine to mannose residues during the synthesis of glycosylphosphatidylinositol (GPI), and essential process for the cell surface localization of GPI-anchored proteins (Inoue et al, 1993, PMID: 8463218; Hong et al, 2000, PMID: 10781593; Shishioh et al, 2005, PMID: 15632136; Kinoshita et al, 2024, PMID: 39129667). GPI-anchored proteins have been shown to be lacking on the cell surface of fibroblasts from patients with OORS, and variants in other genes involved in the GPI synthesis pathway have been identified in patients with overlapping clinical symptoms (Salian et al, 2021, PMID: 33386993). In summary, there is currently limited evidence supporting the relationship between *PIGF* and congenital disorder of glycosylation. This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on November 7, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0859161
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0859161
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; 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 PIGF variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002643.4. 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 | 4 | 4 | ||||
| missense | 38 | 1 | 2 | 41 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 1 | 0 | 38 | 5 | 2 | 46 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002634.1 | 5 | MANE Select | |
| Ensembl | ENSP00000281382.6 | 5 | MANE Select | |
| RefSeq | NP_775097.1 | 5 | Standard | |
| Ensembl | ENSP00000302663.4 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glycosylphosphatidylinositol (GPI)-anchor biosynthesis - Homo sapiens (human)
- VEGF Signaling Pathway
- Exercise-induced Circadian Regulation
- Synthesis of glycosylphosphatidylinositol (GPI)
- Post-translational modification: synthesis of GPI-anchored proteins
Biological Process
- GPI anchor biosynthetic process
- preassembly of GPI anchor in ER membrane
Molecular Function
- ethanolaminephosphotransferase activity
Cellular Component
- endoplasmic reticulum membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000281382
- Coding exons
- 5
- Length
- 36183
- Individuals with no LoFs
- 125696
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 27
- Defined
- 125723
- p
- 0.000107
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.555 | 115 | 99.4 | 1.16 | 0.00000455 | 1382 |
| Missense (PolyPhen) | 33 | 29.39 | 1.1228 | 414 | ||
| Synonymous | -0.0485 | 39 | 38.6 | 1.01 | 0.00000200 | 424 |
| Loss of Function | 1.02 | 6 | 9.35 | 0.642 | 3.93e-7 | 139 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00045 | 0.00043 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000097 | 0.000097 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in GPI-anchor biosynthesis through the transfer of ethanolamine phosphate to the third mannose of GPI. {ECO:0000250}.;
Recessive Scores
- pRec
- 0.148
Intolerance Scores
- LoFtool
- 0.250
- RVIS EVS
- 0.33
- RVIS percentile EVS
- 73.27
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0482
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |