MEFV

MEFV innate immunity regulator, pyrin, the group of Pyrin domain containing|Tripartite motif family

Basic information

Region (hg38): 16:3242026-3256633

Previous symbols: [ "MEF" ]

Links

ENSG00000103313 ∙ NCBI:4210 ∙ OMIM:608107 ∙ HGNC:6998 ∙ Uniprot:O15553 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial Mediterranean fever (Definitive), mode of inheritance: AR
• familial Mediterranean fever (Supportive), mode of inheritance: AD
• autosomal recessive familial Mediterranean fever (Definitive), mode of inheritance: AR
• familial Mediterranean fever, autosomal dominant (Strong), mode of inheritance: AR
• familial Mediterranean fever (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Familial Mediterranean fever; Neutrophilic dermatosis, acute febrile	AD/AR	Allergy/Immunology/Infectious	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.	Allergy/Immunology/Infectious; Dermatologic; Musculoskeletal; Renal	14162896; 4437392; 4636899; 4783424; 921085; 6822630; 3966749; 3306755; 3515182; 3694919; 8434621; 8831074; 9288094; 9288758; 9415347; 9266193; 9450890; 10528243; 10787449; 12130485; 12529300; 14679589; 15024744; 16632148; 20301405; 23075349; 23070486; 23463692; 23508419; 23505238; 23521609; 23710607; 23716950; 23742958; 23800337; 23844200; 27030597; 28835462; 31998953
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

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

• Familial Mediterranean fever (894 variants)
• not provided (286 variants)
• Familial Mediterranean fever, autosomal dominant (223 variants)
• Acute febrile neutrophilic dermatosis (187 variants)
• not specified (166 variants)
• Autoinflammatory syndrome (115 variants)
• Inborn genetic diseases (73 variants)
• Familial Mediterranean fever;Familial Mediterranean fever, autosomal dominant;Acute febrile neutrophilic dermatosis (69 variants)
• Acute febrile neutrophilic dermatosis;Familial Mediterranean fever;Familial Mediterranean fever, autosomal dominant (59 variants)
• Familial Mediterranean fever;Familial Mediterranean fever, autosomal dominant (21 variants)
• MEFV-related condition (8 variants)
• Familial Mediterranean fever, autosomal dominant;Familial Mediterranean fever;Acute febrile neutrophilic dermatosis (8 variants)
• See cases (4 variants)
• Acute febrile neutrophilic dermatosis;Familial Mediterranean fever, autosomal dominant;Familial Mediterranean fever (4 variants)
• Behcet disease (2 variants)
• 8 conditions (2 variants)
• Heart, malformation of;Renal insufficiency;Abnormal cardiovascular system morphology (1 variants)
• MEFV-related disorders (1 variants)
• Recurrent fever (1 variants)
• Central core myopathy (1 variants)
• Neurodevelopmental delay;Skin vesicle;Hyperpigmentation of the skin (1 variants)
• 6 conditions (1 variants)
• 9 conditions (1 variants)
• Familial Mediterranean fever, autosomal dominant;Familial Mediterranean fever (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MEFV 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			9	220	9	238
missense	4	5	285	13	5	312
nonsense	2	2	12	2		18
start loss			1			1
frameshift	1	3	18	1		23
inframe indel			1			1
splice donor/acceptor (+/-2bp)			7			7
splice region			5	17	1	23
non coding			34	67	19	120
Total	7	10	367	303	33

Highest pathogenic variant AF is 0.0000525

Variants in MEFV

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

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

Position	Type	Phenotype	Significance	ClinVar
16-3242045-T-A		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242061-T-C		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242085-C-A		Familial Mediterranean fever	Benign (Jan 13, 2018)
16-3242112-C-G		Familial Mediterranean fever	Uncertain significance (Jan 12, 2018)
16-3242133-T-C		Familial Mediterranean fever	Uncertain significance (Jan 12, 2018)
16-3242139-C-G		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242160-T-C		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242182-A-G		Familial Mediterranean fever	Uncertain significance (Jan 12, 2018)
16-3242279-T-G		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242296-G-A		Familial Mediterranean fever	Uncertain significance (Jan 12, 2018)
16-3242304-C-CAGT		Familial Mediterranean fever	Likely benign (Jun 14, 2016)
16-3242323-T-G		Familial Mediterranean fever	Uncertain significance (Jan 12, 2018)
16-3242344-A-G		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242361-CA-C		Familial Mediterranean fever	Uncertain significance (Jun 14, 2016)
16-3242379-AG-A		Familial Mediterranean fever	Uncertain significance (Jun 14, 2016)
16-3242380-G-C		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242398-A-G		Familial Mediterranean fever	Benign (Jan 12, 2018)
16-3242417-C-T		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242420-A-T		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242440-C-T		Familial Mediterranean fever	Uncertain significance (Jan 12, 2018)
16-3242446-G-C		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242451-C-A		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242462-G-C		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242502-C-T		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)
16-3242562-G-T		Familial Mediterranean fever	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MEFV	protein_coding	protein_coding	ENST00000219596	10	14600

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.02e-14	0.139	125700	0	48	125748	0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.72	551	449	1.23	0.0000288	5003
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000689	0.000689
Ashkenazi Jewish	0.00	0.00
East Asian	0.000326	0.000326
Finnish	0.00	0.00
European (Non-Finnish)	0.0000973	0.0000879
Middle Eastern	0.000326	0.000326
South Asian	0.000490	0.000490
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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;Innate Immune System;Immune System (Consensus)

Recessive Scores

• pRec: 0.214

Intolerance Scores

• loftool: 0.912
• rvis_EVS: 1.19
• rvis_percentile_EVS: 92.85

Haploinsufficiency Scores

• pHI: 0.0876
• hipred: N
• hipred_score: 0.112
• ghis: 0.460

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.428

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mefv
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region 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); liver/biliary system phenotype; immune system phenotype; skeleton phenotype; hematopoietic system 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); normal phenotype; reproductive system phenotype

Gene ontology

• 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;negative regulation of inflammatory response;negative regulation of macrophage inflammatory protein 1 alpha production;negative regulation of cytokine production involved in inflammatory response;negative regulation of NLRP3 inflammasome complex assembly;positive regulation of cysteine-type endopeptidase activity
• Cellular component: ruffle;nucleus;cytoplasm;autophagosome;cytosol;microtubule;microtubule associated complex;lamellipodium;cytoplasmic vesicle
• Molecular function: actin binding;protein binding;zinc ion binding;identical protein binding