MEFV
protein-codingMEFV innate immunity regulator, pyrin, the group of Pyrin domain containing|Tripartite motif family
Gene summary
This gene encodes a protein, also known as pyrin or marenostrin, that is an important modulator of innate immunity. Mutations in this gene are associated with Mediterranean fever, a hereditary periodic fever syndrome. [provided by RefSeq, Jul 2008]
- MEF
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~14.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0018088
Submitter: Myriad Women's Health
Inheritance Pattern: AR
Disease ID:MONDO:0007601
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009572
Submitter: G2P
Inheritance Pattern: SD
Disease ID:MONDO:0018088
Submitter: Natera
Inheritance Pattern: SD
Disease ID:MONDO:0018088
Submitter: ClinGen
Biallelic variants in MEFV were first implicated in autosomal recessive familial Mediterranean fever (FMF) in 1997 (PMIDs:9288094, 9325049). MEFV encodes a pyrin protein (marenostrin) and is involved in innate immunity regulation and inflammatory response (https://www.genecards.org/cgi-bin/carddisp.pl?gene=MEFV). FMF is characterized by recurrent fever, abdominal pain, chest pain, arthralgias, and amyloidosis in some individuals (PMID:20301405). The disorder was originally identified in Mediterranean populations, affecting up to 1 in 500 people in Armenian populations, though individuals with variants in MEFV and features of FMF have also been identified in other populations (PMID:18403822). Individuals with clinical diagnoses of FMF and heterozygous variants in MEFV have also been reported. These individuals have similar phenotypic severity and age of onset as individuals with biallelic variants in MEFV. In earlier literature, limited genetic testing (such as screening of select exons) was performed and the possibility of a second variant in MEFV undetectable via the methodology used could not be ruled out (PMID:32824452). However, more recent studies performed sequencing of the entire gene as well as haplotype analysis (to identify a common haplotype that might be associated with transmission of a second variant), and also failed to identify a second variant (PMID:19479870). The same variants are observed in heterozygous and homozygous affected individuals as well as heterozygous unaffected individuals. Because of this, the General GCEP has decided to curate this gene-disease relationship using a semi-dominant mode of inheritance. Variants from 78 probands across 9 publications are included in this curation (PMIDs:9288094, 28483595, 30171907, 11175300, 29543225, 20937419, 34527104, 19479870, 19479871). Variants are predominantly missense, though nonsense, frameshift, and in-frame indel variants have been observed (https://databases.lovd.nl/shared/genes/MEFV). The proposed disease mechanism is gain of function (PMID:21600797). Segregation of MEFV variants with FMF has been documented within numerous families (PMIDs: 20937419, 11977178). Additional genetic evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The gene-disease relationship between FMF and MEFV is also supported by gene-level experimental evidence. Monocytes from clinically affected individuals with FMF showed increased IL-1β secretion compared to clinically unaffected monocytes (PMID:23505242). Monocytes from clinically diagnosed FMF individuals and unaffected individuals in another study were stimulated with proinflammatory mediators, resulting in increased MEFV mRNA in individuals with FMF (PMID:10807793). Additionally there are three homozygous knock-in mouse models of the most commonly observed variants observed in individuals with FMF that show an inflammatory response of differing severities, depending on the variant, further supporting this relationship (PMID:21600797). In summary, there is definitive evidence supporting a gene-disease relationship between variants in MEFV and semi-dominant familial Mediterranean fever. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Gene Curation Expert Panel on 02/23/2022.
Inheritance Pattern: AD
Disease ID:MONDO:0018088
Submitter: Orphanet
Inheritance Pattern: SD
Disease ID:MONDO:0018088
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Musculoskeletal; Renal
Intervention: Allergy/Immunology/Infectious
Rationale: Individuals with Familial Mediterranean Fever may present with periodic fever, pain (including abdominal pain, arthritis, pleurisy), and rash,and medical treatment aimed at reducing inflammation (eg, with colchicine, TNF-alpha antibodies, IL-1 decoy receptor agents) can be effective (and additional considerations related to medical treatment prior to and during pregnancy may be beneficial); BMT has been reported; Individuals with Neutrophilic dermatosis, acute febrile have been described with pediatric onset of recurrent fever and dermatologic abnormalities, and treatment (eg, with corticosteroids, adalimumab, and TNFA antagonist) has been described as potentially beneficial but not completely effective.
Comments: It has been described that heterozygous mutations, while potentially contributing to/causing certain autoinflammatory disorders, do not cause classic (Mendelian) Familial Mediterranean fever, but may act as risk alleles (susceptibility factors) for clinically similar forms of disease
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MEFV variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000243.3. 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 | 6 | 387 | 26 | 419 | ||
| missense | 4 | 23 | 455 | 140 | 1 | 623 |
| nonsense | 2 | 3 | 16 | 6 | 27 | |
| start loss | 1 | 1 | ||||
| frameshift | 1 | 5 | 28 | 3 | 37 | |
| splice donor/acceptor (+/-2bp) | 1 | 10 | 11 | |||
| Total | 7 | 32 | 516 | 536 | 27 | 1118 |
Highest pathogenic variant AF is 0.0016448876
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000234.1 | 10 | MANE Select | |
| Ensembl | ENSP00000219596.1 | 10 | MANE Select | |
| RefSeq | NP_001185465.2 | 9 | Standard | |
| Ensembl | ENSP00000339639.4 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- NOD-like receptor signaling pathway - Homo sapiens (human)
- Nucleotide-binding Oligomerization Domain (NOD) pathway
- The NLRP3 inflammasome
- Inflammasomes
- Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
Biological Process
- inflammatory response
- positive regulation of autophagy
- negative regulation of interleukin-1 beta production
- negative regulation of interleukin-12 production
- response to interferon-gamma
Molecular Function
- actin binding
- protein binding
- zinc ion binding
- identical protein binding
Cellular Component
- ruffle
- nucleus
- cytoplasm
- autophagosome
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000219596
- Coding exons
- 10
- Length
- 14600
- Individuals with no LoFs
- 125700
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 48
- Defined
- 125748
- p
- 0.000191
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.72 | 551 | 449 | 1.23 | 0.0000288 | 5003 |
| Missense (PolyPhen) | 120 | 108.87 | 1.1022 | 1441 | ||
| Synonymous | -2.50 | 242 | 197 | 1.23 | 0.0000136 | 1600 |
| Loss of Function | 0.986 | 25 | 30.9 | 0.809 | 0.00000149 | 374 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00037 | 0.00037 | rare |
| Latino/Admixed American | 0.00032 | 0.00032 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000097 | 0.000088 | rare |
| South Asian | 0.00049 | 0.00049 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1, ATG16L1, and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy. Acts as an autophagy receptor for the degradation of several inflammasome components, including CASP1, NLRP1 and NLRP3, hence preventing excessive IL1B- and IL18- mediated inflammation (PubMed:16785446, PubMed:17431422, PubMed:26347139). However, it may also have a positive effect in the inflammatory pathway. In different experimental systems, it has been shown to activate IL1B production (PubMed:16037825). It has also been shown to be required for PSTPIP1-induced PYCARD oligomerization and for formation of inflammasomes. Recruits PSTPIP1 to inflammasomes, and is required for PSTPIP1 oligomerization (PubMed:10807793, PubMed:11468188, PubMed:17964261, PubMed:18577712, PubMed:19109554, PubMed:19584923). {ECO:0000269|PubMed:10807793, ECO:0000269|PubMed:11468188, ECO:0000269|PubMed:16037825, ECO:0000269|PubMed:16785446, ECO:0000269|PubMed:17431422, ECO:0000269|PubMed:17964261, ECO:0000269|PubMed:18577712, ECO:0000269|PubMed:19109554, ECO:0000269|PubMed:19584923, ECO:0000269|PubMed:26347139}.;
- Disease
- DISEASE: Familial Mediterranean fever, autosomal recessive (ARFMF) [MIM:249100]: A hereditary periodic fever syndrome characterized by recurrent episodic fever, serosal inflammation and pain in the abdomen, chest or joints. It is frequently complicated by reactive amyloidosis, which leads to renal failure and can be prophylactically treated with colchicine. {ECO:0000269|PubMed:10024914, ECO:0000269|PubMed:10090880, ECO:0000269|PubMed:10234504, ECO:0000269|PubMed:10364520, ECO:0000269|PubMed:10612841, ECO:0000269|PubMed:10842288, ECO:0000269|PubMed:10854105, ECO:0000269|PubMed:11470495, ECO:0000269|PubMed:15024744, ECO:0000269|PubMed:16378925, ECO:0000269|PubMed:16730661, ECO:0000269|PubMed:23031807, ECO:0000269|PubMed:24929125, ECO:0000269|PubMed:26347139, ECO:0000269|PubMed:9288094, ECO:0000269|PubMed:9288758, ECO:0000269|PubMed:9668175}. Note=The disease is caused by mutations affecting the gene represented in this entry. The disease-associated mutations in the B30.2/SPRY domain perturb ULK1 recruitment and autophagic degradation of inflammasome components, including NLRP3, and hence may contribute to the inflammatory phenotype associated with ARFMF. {ECO:0000269|PubMed:26347139}.; DISEASE: Familial Mediterranean fever, autosomal dominant (ADFMF) [MIM:134610]: A hereditary periodic fever syndrome characterized by periodic fever, serosal inflammation and pain in the abdomen, chest or joints as seen also in the autosomal recessive form of the disease. It is associated with reactive renal amyloidosis and characterized by colchicine unresponsiveness. {ECO:0000269|PubMed:10787449, ECO:0000269|PubMed:14679589}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.214
Intolerance Scores
- LoFtool
- 0.912
- RVIS EVS
- 1.19
- RVIS percentile EVS
- 92.85
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.428
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |