NLRP3
NLR family pyrin domain containing 3, the group of NLR family|Pyrin domain containing
Basic information
Region (hg38): 1:247332331-247449108
Previous symbols: [ "C1orf7", "CIAS1", "DFNA34" ]
Links
Phenotypes
GenCC
Source:
- CINCA syndrome (Strong), mode of inheritance: AD
- keratitis fugax hereditaria (Limited), mode of inheritance: AD
- Muckle-Wells syndrome (Supportive), mode of inheritance: AD
- CINCA syndrome (Supportive), mode of inheritance: AD
- familial cold autoinflammatory syndrome (Supportive), mode of inheritance: AD
- CINCA syndrome (Definitive), mode of inheritance: AD
- familial cold autoinflammatory syndrome 1 (Strong), mode of inheritance: AD
- cryopyrin-associated periodic syndrome (Definitive), mode of inheritance: AD
- CINCA syndrome (Strong), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Chronic Infantile Neurologic Cutaneous Articular (CINCA) syndrome; Deafness, autosomal dominant, 34, with or without inflammation; Muckle-Wells syndrome; Neonatal Onset Multisystem Inflammatory Disease (NOMID); Familial cold-induced autoinflammatory syndrome 1 | AD | Allergy/Immunology/Infectious | Individuals may present with autoinflammatory manifestions, which can be severe, progressive, and ultimately fatal, medical treatment with IL1R antagonists (eg, anakinra, canakinumab) has been described as an effective treatment; In Familial cold-induced autoinflammatory syndrome 1, medical management (eg, with stanozolol) has been described as beneficial | Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Dermatologic; Ophthalmologic; Renal | 14476827; 5769632; 5173311; 49161; 447320; 8447672; 11687797; 12032915; 12483741; 11992256; 12928894; 16532456; 21356079; 21538043; 21859692; 21967869; 22193915; 22723549; 28847925; 29366613 |
ClinVar
This is a list of variants' phenotypes submitted to
- Cryopyrin associated periodic syndrome (17 variants)
- Familial cold autoinflammatory syndrome 1 (13 variants)
- not provided (10 variants)
- Familial amyloid nephropathy with urticaria AND deafness (4 variants)
- Chronic infantile neurological, cutaneous and articular syndrome (2 variants)
- Autoinflammatory syndrome (2 variants)
- Chronic infantile neurological, cutaneous and articular syndrome;Familial amyloid nephropathy with urticaria AND deafness (1 variants)
- not specified (1 variants)
- Hearing loss, autosomal dominant 34, with or without inflammation;Keratitis fugax hereditaria;Chronic infantile neurological, cutaneous and articular syndrome;Familial amyloid nephropathy with urticaria AND deafness;Familial cold autoinflammatory syndrome 1 (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the NLRP3 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 | 14 | 206 | 13 | 233 | ||
| missense | 20 | 28 | 365 | 10 | 423 | |
| nonsense | 12 | 13 | ||||
| start loss | 0 | |||||
| frameshift | 4 | |||||
| inframe indel | 3 | |||||
| splice donor/acceptor (+/-2bp) | 3 | |||||
| splice region | 10 | 18 | 1 | 29 | ||
| non coding | 28 | 48 | 57 | 133 | ||
| Total | 21 | 28 | 429 | 264 | 70 |
Variants in NLRP3
This is a list of pathogenic ClinVar variants found in the NLRP3 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 1-247417746-A-G | Lung adenocarcinoma | Uncertain significance (Jun 06, 2022) | ||
| 1-247418091-C-T | Familial amyloid nephropathy with urticaria AND deafness • Chronic infantile neurological, cutaneous and articular syndrome • Familial cold autoinflammatory syndrome 1 | Uncertain significance (Jan 13, 2018) | ||
| 1-247418115-C-T | Familial cold autoinflammatory syndrome 1 • Familial amyloid nephropathy with urticaria AND deafness • Chronic infantile neurological, cutaneous and articular syndrome | Uncertain significance (Jan 13, 2018) | ||
| 1-247418116-G-A | Familial amyloid nephropathy with urticaria AND deafness • Chronic infantile neurological, cutaneous and articular syndrome • Familial cold autoinflammatory syndrome 1 | Uncertain significance (Jan 13, 2018) | ||
| 1-247418172-C-T | Chronic infantile neurological, cutaneous and articular syndrome • Familial amyloid nephropathy with urticaria AND deafness • Familial cold autoinflammatory syndrome 1 | Uncertain significance (Jan 13, 2018) | ||
| 1-247418240-T-G | Chronic infantile neurological, cutaneous and articular syndrome • Familial amyloid nephropathy with urticaria AND deafness • Familial cold autoinflammatory syndrome 1 | Benign (Jan 13, 2018) | ||
| 1-247418258-A-T | Familial amyloid nephropathy with urticaria AND deafness • Familial cold autoinflammatory syndrome 1 • Chronic infantile neurological, cutaneous and articular syndrome | Benign (Jan 13, 2018) | ||
| 1-247418268-C-G | Familial amyloid nephropathy with urticaria AND deafness • Chronic infantile neurological, cutaneous and articular syndrome • Familial cold autoinflammatory syndrome 1 | Uncertain significance (Jan 12, 2018) | ||
| 1-247418268-C-T | Familial amyloid nephropathy with urticaria AND deafness • Chronic infantile neurological, cutaneous and articular syndrome • Familial cold autoinflammatory syndrome 1 | Benign (Jan 12, 2018) | ||
| 1-247418278-G-A | Familial cold autoinflammatory syndrome 1 • Familial amyloid nephropathy with urticaria AND deafness • Chronic infantile neurological, cutaneous and articular syndrome | Uncertain significance (Jan 12, 2018) | ||
| 1-247418307-C-CT | Chronic infantile neurological, cutaneous and articular syndrome • Familial cold autoinflammatory syndrome • Familial amyloid nephropathy with urticaria AND deafness | Uncertain significance (Jun 14, 2016) | ||
| 1-247418341-G-A | Familial amyloid nephropathy with urticaria AND deafness • Familial cold autoinflammatory syndrome 1 • Chronic infantile neurological, cutaneous and articular syndrome | Uncertain significance (Jan 13, 2018) | ||
| 1-247418390-T-C | Familial cold autoinflammatory syndrome 1 • Chronic infantile neurological, cutaneous and articular syndrome • Familial amyloid nephropathy with urticaria AND deafness | Benign (Jan 13, 2018) | ||
| 1-247418394-C-T | Familial cold autoinflammatory syndrome 1 • Chronic infantile neurological, cutaneous and articular syndrome • Familial amyloid nephropathy with urticaria AND deafness | Uncertain significance (Jan 12, 2018) | ||
| 1-247418432-G-A | Chronic infantile neurological, cutaneous and articular syndrome • Familial amyloid nephropathy with urticaria AND deafness • Familial cold autoinflammatory syndrome 1 | Uncertain significance (Jan 13, 2018) | ||
| 1-247418462-C-T | Chronic infantile neurological, cutaneous and articular syndrome • Familial cold autoinflammatory syndrome 1 • Familial amyloid nephropathy with urticaria AND deafness | Uncertain significance (Jan 12, 2018) | ||
| 1-247418570-G-A | Chronic infantile neurological, cutaneous and articular syndrome • Familial amyloid nephropathy with urticaria AND deafness • Familial cold autoinflammatory syndrome 1 | Benign (Jan 13, 2018) | ||
| 1-247418582-G-A | Familial amyloid nephropathy with urticaria AND deafness • Familial cold autoinflammatory syndrome 1 • Chronic infantile neurological, cutaneous and articular syndrome | Uncertain significance (Jan 13, 2018) | ||
| 1-247418598-G-A | Familial cold autoinflammatory syndrome 1 • Familial amyloid nephropathy with urticaria AND deafness • Chronic infantile neurological, cutaneous and articular syndrome | Uncertain significance (Jan 12, 2018) | ||
| 1-247418655-T-C | Lung adenocarcinoma | Uncertain significance (Jun 06, 2022) | ||
| 1-247418679-T-C | Familial cold autoinflammatory syndrome 1 • Chronic infantile neurological, cutaneous and articular syndrome • Familial amyloid nephropathy with urticaria AND deafness | Conflicting classifications of pathogenicity (Jan 01, 2023) | ||
| 1-247418680-T-C | Lung adenocarcinoma | Uncertain significance (Jun 06, 2022) | ||
| 1-247418722-C-T | Benign (Mar 03, 2015) | |||
| 1-247418727-G-A | Familial cold autoinflammatory syndrome 1 • Chronic infantile neurological, cutaneous and articular syndrome • Familial amyloid nephropathy with urticaria AND deafness | Uncertain significance (Jan 13, 2018) | ||
| 1-247418729-G-A | not specified | Uncertain significance (Dec 18, 2018) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| NLRP3 | protein_coding | protein_coding | ENST00000336119 | 9 | 32953 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.000811 | 0.999 | 125715 | 0 | 33 | 125748 | 0.000131 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 2.14 | 414 | 556 | 0.744 | 0.0000333 | 6854 |
| Missense in Polyphen | 123 | 206.94 | 0.59436 | 2670 | ||
| Synonymous | -3.41 | 301 | 235 | 1.28 | 0.0000153 | 1958 |
| Loss of Function | 3.94 | 13 | 39.8 | 0.326 | 0.00000226 | 483 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.0000869 | 0.0000869 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.000163 | 0.000109 |
| Finnish | 0.000416 | 0.000416 |
| European (Non-Finnish) | 0.000141 | 0.000141 |
| Middle Eastern | 0.000163 | 0.000109 |
| South Asian | 0.0000982 | 0.0000980 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: As the sensor component of the NLRP3 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP3, PYCARD and CASP1 (and possibly CASP4 and CASP5). Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1- catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. Activation of NLRP3 inflammasome is also required for HMGB1 secretion (PubMed:22801494). The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death. Under resting conditions, NLRP3 is autoinhibited. NLRP3 activation stimuli include extracellular ATP, reactive oxygen species, K(+) efflux, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, cytosolic dsRNA, etc. However, it is unclear what constitutes the direct NLRP3 activator. Activation in presence of cytosolic dsRNA is mediated by DHX33 (PubMed:23871209). Independently of inflammasome activation, regulates the differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-dependent asthma and tumor growth (By similarity). During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription. Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (By similarity). {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:23871209, ECO:0000305|PubMed:23305783}.;
- Disease
- DISEASE: Familial cold autoinflammatory syndrome 1 (FCAS1) [MIM:120100]: A rare autosomal dominant systemic inflammatory disease characterized by recurrent episodes of maculopapular rash associated with arthralgias, myalgias, fever and chills, swelling of the extremities, and conjunctivitis after generalized exposure to cold. Rarely, some patients may also develop late-onset renal amyloidosis. {ECO:0000269|PubMed:11687797, ECO:0000269|PubMed:11992256, ECO:0000269|PubMed:12355493, ECO:0000269|PubMed:12522564, ECO:0000269|PubMed:15593220, ECO:0000269|PubMed:17284928, ECO:0000269|PubMed:24952504}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muckle-Wells syndrome (MWS) [MIM:191900]: A hereditary periodic fever syndrome characterized by fever, chronic recurrent urticaria, arthralgias, progressive sensorineural deafness, and reactive renal amyloidosis. The disease may be severe if generalized reactive amyloidosis occurs. {ECO:0000269|PubMed:11687797, ECO:0000269|PubMed:11992256, ECO:0000269|PubMed:12355493, ECO:0000269|PubMed:15593220, ECO:0000269|PubMed:24952504}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Chronic infantile neurologic cutaneous and articular syndrome (CINCA) [MIM:607115]: Rare congenital inflammatory disorder characterized by a triad of neonatal onset of cutaneous symptoms, chronic meningitis, and joint manifestations with recurrent fever and inflammation. {ECO:0000269|PubMed:12032915, ECO:0000269|PubMed:12483741, ECO:0000269|PubMed:14630794, ECO:0000269|PubMed:15231984, ECO:0000269|PubMed:15334500, ECO:0000269|PubMed:15593220, ECO:0000269|PubMed:24952504}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Keratoendothelitis fugax hereditaria (KEFH) [MIM:148200]: An autosomal dominant corneal disease that periodically, and fleetingly, affects the corneal endothelium, stroma, and vision, eventually leading to central corneal stromal opacities in some patients. The disease is characterized by unilateral attacks of ocular pain, pericorneal injection, and photophobia. The acute symptoms vanish in 1-2 days but vision remains blurry for several weeks. The attacks start at the age of 3-12 years and can affect either eye. They generally decrease in frequency and get milder with age. {ECO:0000269|PubMed:29366613}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Pertussis - Homo sapiens (human);Influenza A - Homo sapiens (human);Necroptosis - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Nucleotide-binding Oligomerization Domain (NOD) pathway;IL1 and megakaryocytes in obesity;The NLRP3 inflammasome;Inflammasomes;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;Post-translational protein modification;Metabolism of proteins;Innate Immune System;Immune System;Metalloprotease DUBs;Deubiquitination
(Consensus)
Recessive Scores
- pRec
- 0.105
Intolerance Scores
- loftool
- 0.00351
- rvis_EVS
- -0.95
- rvis_percentile_EVS
- 9.38
Haploinsufficiency Scores
- pHI
- 0.417
- hipred
- Y
- hipred_score
- 0.655
- ghis
- 0.443
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.848
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Nlrp3
- Phenotype
- hematopoietic 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); reproductive system phenotype; liver/biliary system phenotype; skeleton phenotype; renal/urinary system phenotype; immune system phenotype; digestive/alimentary phenotype; limbs/digits/tail phenotype; 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); 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); homeostasis/metabolism phenotype; cellular phenotype;
Gene ontology
- Biological process
- cytokine secretion involved in immune response;negative regulation of acute inflammatory response;positive regulation of type 2 immune response;apoptotic process;activation of cysteine-type endopeptidase activity involved in apoptotic process;defense response;inflammatory response;signal transduction;detection of biotic stimulus;protein deubiquitination;negative regulation of NF-kappaB transcription factor activity;interleukin-1 beta production;interleukin-18 production;positive regulation of interleukin-13 production;positive regulation of interleukin-4 production;positive regulation of interleukin-5 production;positive regulation of cysteine-type endopeptidase activity involved in apoptotic process;NLRP3 inflammasome complex assembly;innate immune response;positive regulation of T-helper 2 cell differentiation;positive regulation of transcription by RNA polymerase II;interleukin-1 secretion;negative regulation of interleukin-1 beta secretion;positive regulation of interleukin-1 beta secretion;negative regulation of inflammatory response;defense response to Gram-positive bacterium;positive regulation of NF-kappaB transcription factor activity;protein complex oligomerization;defense response to virus;cellular response to lipopolysaccharide;cellular response to peptidoglycan;negative regulation of NIK/NF-kappaB signaling;positive regulation of T-helper 17 cell differentiation;positive regulation of T-helper 2 cell cytokine production
- Cellular component
- extracellular region;nucleus;cytoplasm;endoplasmic reticulum;cytosol;NLRP3 inflammasome complex
- Molecular function
- protein binding;ATP binding;transcription factor binding;identical protein binding;peptidoglycan binding;sequence-specific DNA binding