PRF1

perforin 1, the group of C2 domain containing

Basic information

Region (hg38): 10:70597348-70602759

Links

ENSG00000180644 ∙ NCBI:5551 ∙ OMIM:170280 ∙ HGNC:9360 ∙ Uniprot:P14222 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary hemophagocytic lymphohistiocytosis (Supportive), mode of inheritance: AR
• fatal post-viral neurodegenerative disorder (Supportive), mode of inheritance: AR
• familial hemophagocytic lymphohistiocytosis 2 (Strong), mode of inheritance: AR
• lymphoma, non-Hodgkin, familial (Limited), mode of inheritance: Unknown
• familial hemophagocytic lymphohistiocytosis 2 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hemophagocytic lymphohistiocytosis, familial, 2; Lymphoma, non-Hodgkin; Aplastic anemia, adult-onset	AR	Allergy/Immunology/Infectious; Hematologic; Oncologic	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	Allergy/Immunology/Infectious; Hematologic; Oncologic	10583959; 12229880; 12358924; 14757862; 15659737; 17311987; 15728124; 17873118; 21936944; 21959744; 22029169; 22186995; 22359105; 23443029; 32374962
Individuals with Aplastic anemia, adult-onset may have manifestations after the pediatric period

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PRF1 gene.

• Familial hemophagocytic lymphohistiocytosis 2 (54 variants)
• Aplastic anemia (26 variants)
• Familial hemophagocytic lymphohistiocytosis (9 variants)
• not provided (5 variants)
• Inborn genetic diseases (4 variants)
• Autoinflammatory syndrome (2 variants)
• PRF1-related disorder (2 variants)
• Aplastic anemia;Familial hemophagocytic lymphohistiocytosis 2;Lymphoma, non-Hodgkin, familial (1 variants)
• Lymphoma, non-Hodgkin, familial;Aplastic anemia;Familial hemophagocytic lymphohistiocytosis 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PRF1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	210	4	215
missense	13	27	226	3		269
nonsense	20	14				34
start loss	1	2	1			4
frameshift	27	15				42
inframe indel	1	1	1			3
splice donor/acceptor (+/-2bp)		2	1			3
splice region			1	4		5
non coding			17	13	8	38
Total	62	61	247	226	12

Highest pathogenic variant AF is 0.000880

Variants in PRF1

This is a list of pathogenic ClinVar variants found in the PRF1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
10-70597389-T-C		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Jan 13, 2018)
10-70597494-A-C		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Jan 13, 2018)
10-70597513-A-G		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Jan 12, 2018)
10-70597532-G-T		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Jan 13, 2018)
10-70597567-A-G		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Jan 12, 2018)
10-70597612-C-T		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Jan 12, 2018)
10-70597677-C-T		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Jan 12, 2018)
10-70597686-C-T		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Jan 13, 2018)
10-70597687-G-A		Familial hemophagocytic lymphohistiocytosis 2	Likely benign (Apr 27, 2017)
10-70597843-TA-T		Familial hemophagocytic lymphohistiocytosis • not specified	Benign (Jan 24, 2024)
10-70597843-TAA-T			Benign (Jun 19, 2021)
10-70597860-T-C		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Jan 12, 2018)
10-70597877-T-A		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Mar 23, 2018)
10-70597879-A-G		Familial hemophagocytic lymphohistiocytosis 2	Likely benign (Jan 13, 2018)
10-70597914-G-A		Familial hemophagocytic lymphohistiocytosis 2	Benign (Apr 27, 2017)
10-70597914-G-T		Familial hemophagocytic lymphohistiocytosis 2	Benign (Jan 13, 2018)
10-70597941-C-T		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Jan 12, 2018)
10-70597957-C-T		Familial hemophagocytic lymphohistiocytosis 2 • not specified	Benign (Nov 14, 2023)
10-70597964-G-A		Familial hemophagocytic lymphohistiocytosis 2	Benign (Nov 12, 2018)
10-70598007-A-G		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Jan 12, 2018)
10-70598061-C-T		Familial hemophagocytic lymphohistiocytosis 2	Uncertain significance (Aug 27, 2021)
10-70598062-G-A		Familial hemophagocytic lymphohistiocytosis 2	Likely benign (Jan 22, 2024)
10-70598071-C-A		Familial hemophagocytic lymphohistiocytosis 2	Likely benign (Oct 30, 2023)
10-70598071-C-G		Familial hemophagocytic lymphohistiocytosis 2	Likely benign (Oct 30, 2023)
10-70598073-G-A		Inborn genetic diseases	Uncertain significance (Jul 09, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PRF1	protein_coding	protein_coding	ENST00000441259	2	5428

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000549	0.686	125655	0	92	125747	0.000366

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0167	351	352	0.997	0.0000238	3570
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00354	0.00320
Ashkenazi Jewish	0.000397	0.000397
East Asian	0.000386	0.000381
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.000162	0.000158
Middle Eastern	0.000386	0.000381
South Asian	0.000196	0.000196
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Natural killer cell mediated cytotoxicity - Homo sapiens (human);Apoptosis - Homo sapiens (human);Allograft Rejection;Nanomaterial induced apoptosis;Apoptosis;Apoptotic Signaling Pathway;caspase cascade in apoptosis;granzyme a mediated apoptosis pathway;IL12 signaling mediated by STAT4;Caspase Cascade in Apoptosis;IL2 signaling events mediated by STAT5;Downstream signaling in naïve CD8+ T cells;TCR signaling in naïve CD8+ T cells (Consensus)

Recessive Scores

• pRec: 0.574

Intolerance Scores

• loftool: 0.0351
• rvis_EVS: -0.62
• rvis_percentile_EVS: 17.45

Haploinsufficiency Scores

• pHI: 0.0543
• hipred: N
• hipred_score: 0.146
• ghis: 0.452

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.539

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Prf1
• Phenotype: liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); neoplasm; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); immune system phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: immunological synapse formation;T cell mediated cytotoxicity;defense response to tumor cell;immune response to tumor cell;apoptotic process;cellular defense response;cytolysis;protein homooligomerization;defense response to virus;positive regulation of killing of cells of other organism;transmembrane transport
• Cellular component: extracellular region;cytosol;plasma membrane;membrane;integral component of membrane;endosome lumen;cytolytic granule
• Molecular function: calcium ion binding;protein binding;wide pore channel activity;identical protein binding