PRF1
protein-codingperforin 1, the group of C2 domain containing
Gene summary
This gene encodes a protein with structural similarities to complement component C9 that is important in immunity. This protein forms membrane pores that allow the release of granzymes and subsequent cytolysis of target cells. Whether pore formation occurs in the plasma membrane of target cells or in an endosomal membrane inside target cells is subject to debate. Mutations in this gene are associated with a variety of human disease including diabetes, multiple sclerosis, lymphomas, autoimmune lymphoproliferative syndrome (ALPS), aplastic anemia, and familial hemophagocytic lymphohistiocytosis type 2 (FHL2), a rare and lethal autosomal recessive disorder of early childhood. [provided by RefSeq, Aug 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0018316
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0015541
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011337
Submitter: ClinGen
Perforin, encoded by *PRF1*, is a pore-forming protein that polymerizes and forms a channel in the target cell membrane. In the presence of calcium, it penetrates the membrane of the target cell, where it polymerizes to form a cell death–inducing pore. Mutations in the gene encoding perforin, *PRF1*, were first associated with the hyperinflammatory syndrome hemophagocytic lymphohistiocytosis (HLH) in 1999 (PMID: 10583959). Since the first report, more than 100 different mutations in *PRF1* have been described (PMIDs: 14757862, 17873118, 26342526, 32542393, 33746956). Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune dysregulation. Clinical and laboratory signs of HLH reflect intense inflammation, caused by defective eradication of infected target cells and inability to maintain immune homeostasis through killing of activated immune cells (PMID: 26184781). HLH is classified as familial (FHL) when associated with biallelic mutation in one of a set of functionally related genes or with familial recurrence (PMID: 33746956). We scored six *PRF1* variants (nonsense, frameshift, and missense) that have been reported in multiple publications (PMIDs: 10583959, 11179007, 14757862, 15365097, 15741215, 16860143, 26342526 32542393). Mechanism of pathogenicity seems to be biallelic loss of function. Both homozygous and compound heterozygous patients were reported. Patients with a monoallelic mutation, and a partial degranulation defect were also reported but not scored in this curation (PMID: 26342526). Experimental evidence also supports this gene-disease relationship. Single cell expression analysis revealed that perforin is selectively expressed in cytotoxic T lymphocytes and NK cells. Little or no perforin in the granules of the patients studied compared to control cells was detected by immunostaining (PMID: 10583959). Whereas RBL cells that showed wild-type perforin (67 kD) expression, efficiently killed Jurkat target cells to which they were conjugated, *prf1* mutant cells showed expression of a truncated ( approximately 45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules (PMID: 15365097). In summary, there is definitive evidence supporting a gene-disease relationship between variants in *PRF1* and Familial Hemophagocytic Lymphohistiocytosis 2. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Primary Immune Regulatory Disorders GCEP on August 15, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0015909
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011337
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0011508
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011337
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic; Oncologic
Intervention: Allergy/Immunology/Infectious; Hematologic; Oncologic
Rationale: In Lymphoma, non-Hodgkin; Aplastic anemia, adult-onset, surveillance and early treatment of hematologic (eg, anemia, bone marrow failure) and malignant complications may reduce morbidity; In Hemophagocytic lymphohistiocytosis, familial, 2 (as well as Immune-mediated neurodegeneration, infection triggered, at least theoretically), antibiotics or antiviral agents can be beneficial to treat/prevent infections that can trigger an exaggerated inflammatory response; Chemo/immunotherapy has been reported as beneficial, and can achieve clinical stability prior to allogeneic HSCT, which can be effective
Comments: Individuals with Aplastic anemia, adult-onset may have manifestations after the pediatric period
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PRF1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001083116.3. 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 | 254 | 1 | 256 | ||
| missense | 12 | 63 | 277 | 20 | 2 | 374 |
| nonsense | 18 | 25 | 43 | |||
| start loss | 2 | 2 | 1 | 5 | ||
| frameshift | 30 | 22 | 52 | |||
| splice donor/acceptor (+/-2bp) | 2 | 3 | 5 | |||
| Total | 62 | 114 | 282 | 274 | 3 | 735 |
Highest pathogenic variant AF is 0.00016405362
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001076585.1 | 2 | MANE Select | |
| Ensembl | ENSP00000398568.1 | 2 | MANE Select | |
| RefSeq | NP_005032.2 | 2 | Standard | |
| Ensembl | ENSP00000362305.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Type I diabetes mellitus - Homo sapiens (human)
- Allograft rejection - Homo sapiens (human)
- Graft-versus-host disease - Homo sapiens (human)
- Viral myocarditis - Homo sapiens (human)
- Autoimmune thyroid disease - Homo sapiens (human)
Biological Process
- immunological synapse formation
- T cell mediated cytotoxicity
- defense response to tumor cell
- immune response to tumor cell
- apoptotic process
Molecular Function
- calcium ion binding
- protein binding
- wide pore channel activity
- identical protein binding
Cellular Component
- extracellular region
- cytosol
- plasma membrane
- membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000441259
- Coding exons
- 2
- Length
- 5428
- Individuals with no LoFs
- 125655
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 92
- Defined
- 125747
- p
- 0.000366
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0167 | 351 | 352 | 0.997 | 0.0000238 | 3570 |
| Missense (PolyPhen) | 84 | 90.165 | 0.93163 | 1004 | ||
| Synonymous | -0.385 | 163 | 157 | 1.04 | 0.0000107 | 1211 |
| Loss of Function | 1.05 | 10 | 14.3 | 0.701 | 7.09e-7 | 137 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0033 | 0.0030 | notable |
| Latino/Admixed American | 0.00024 | 0.00023 | rare |
| Ashkenazi Jewish | 0.00040 | 0.00040 | rare |
| East Asian | 0.00039 | 0.00038 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a key role in secretory granule-dependent cell death, and in defense against virus-infected or neoplastic cells. Plays an important role in killing other cells that are recognized as non-self by the immune system, e.g. in transplant rejection or some forms of autoimmune disease. Can insert into the membrane of target cells in its calcium-bound form, oligomerize and form large pores. Promotes cytolysis and apoptosis of target cells by facilitating the uptake of cytotoxic granzymes. {ECO:0000269|PubMed:20038786, ECO:0000269|PubMed:20225066, ECO:0000269|PubMed:20889983, ECO:0000269|PubMed:21037563, ECO:0000269|PubMed:9058810, ECO:0000269|PubMed:9164947}.;
- Disease
- DISEASE: Familial hemophagocytic lymphohistiocytosis 2 (FHL2) [MIM:603553]: A rare disorder characterized by immune dysregulation with hypercytokinemia, defective function of natural killer cell, and massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently neurological abnormalities ranging from irritability and hypotonia to seizures, cranial nerve deficits and ataxia. {ECO:0000269|PubMed:10583959, ECO:0000269|PubMed:11179007}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.574
Intolerance Scores
- LoFtool
- 0.0351
- RVIS EVS
- -0.62
- RVIS percentile EVS
- 17.45
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.539
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |