NLRP1

NLR family pyrin domain containing 1, the group of NLR family|Pyrin domain containing|Caspase recruitment domain containing

Basic information

Region (hg38): 17:5499415-5619424

Previous symbols: [ "NALP1", "SLEV1" ]

Links

ENSG00000091592 ∙ NCBI:22861 ∙ OMIM:606636 ∙ HGNC:14374 ∙ Uniprot:Q9C000 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autoinflammation with arthritis and dyskeratosis (Limited), mode of inheritance: Semidominant
• corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome (Moderate), mode of inheritance: Semidominant
• corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome (Supportive), mode of inheritance: AD
• autoinflammation with arthritis and dyskeratosis (Strong), mode of inheritance: AR
• corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Palmoplantar carcinoma, multiple self-healing; Autoinflammation with arthritis and dyskeratosis	AD/AR	Hematologic; Oncologic	Palmoplantar carcinoma involves recurrent palmoplantar, conjunctival, and corneal keratoacanthomas, and individuals have been described as having high susceptibility to malignant squamous cell carcinoma; Features of Autoinflammation with arthritis and dyskeratosis have been described as including anemia severe enough to necessitate splenectomy, and awareness may allow prompt diagnosis and management; Individuals were not reported to benefit from Vitamin A supplementation	Allergy/Immunology/Infectious; Dermatologic; Hematologic; Musculoskeletal; Oncologic; Ophthalmologic	23349227; 27662089; 27965258

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NLRP1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NLRP1 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	205	25	231
missense		2	469	17	22	510
nonsense			17			17
start loss						0
frameshift			23			23
inframe indel			8			8
splice donor/acceptor (+/-2bp)			11			11
splice region			13	28		41
non coding			5	57	12	74
Total	0	2	534	279	59

Variants in NLRP1

This is a list of pathogenic ClinVar variants found in the NLRP1 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-5500619-T-C		not specified	Uncertain significance (Oct 05, 2021)
17-5500827-A-C		not specified	Uncertain significance (Jun 10, 2021)
17-5500833-A-C		not specified	Uncertain significance (Jun 10, 2021)
17-5501463-A-T			not provided (-)
17-5514755-C-T			Likely benign (Aug 07, 2023)
17-5514760-G-C			Uncertain significance (Mar 11, 2022)
17-5514769-C-G			Likely benign (Nov 07, 2023)
17-5514771-GGAGTCC-G		Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome	Uncertain significance (Apr 04, 2024)
17-5514773-A-T			Uncertain significance (Jul 10, 2023)
17-5514777-C-T		Inborn genetic diseases	Uncertain significance (Feb 13, 2024)
17-5514780-T-C			Uncertain significance (Nov 09, 2023)
17-5514787-G-A			Benign (Jan 31, 2024)
17-5514805-C-G		Inborn genetic diseases	Uncertain significance (Mar 07, 2024)
17-5514818-G-A			Uncertain significance (Jun 20, 2023)
17-5514829-C-T			Benign (Jan 19, 2024)
17-5514850-A-T			Uncertain significance (Aug 23, 2022)
17-5514863-C-T		NLRP1-related disorder	Uncertain significance (Dec 07, 2023)
17-5514864-G-A			Uncertain significance (Jul 29, 2023)
17-5514874-C-A			Uncertain significance (Aug 04, 2023)
17-5514884-C-A			Uncertain significance (Dec 24, 2021)
17-5514888-A-C			Uncertain significance (Sep 10, 2022)
17-5514896-C-G			Uncertain significance (Jul 21, 2023)
17-5514896-C-T			Uncertain significance (Nov 22, 2023)
17-5514897-G-T			Likely benign (Apr 28, 2023)
17-5514908-G-A			Uncertain significance (Jun 20, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NLRP1	protein_coding	protein_coding	ENST00000572272	17	119998

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.97e-19	0.971	125679	0	69	125748	0.000274

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.49	685	804	0.852	0.0000447	9517
Missense in Polyphen		148	213.78	0.69231		2890
Synonymous	0.621	323	338	0.957	0.0000195	2987
Loss of Function	2.60	39	60.9	0.640	0.00000303	686

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000564	0.000561
Ashkenazi Jewish	0.00	0.00
East Asian	0.000761	0.000761
Finnish	0.0000927	0.0000924
European (Non-Finnish)	0.000258	0.000255
Middle Eastern	0.000761	0.000761
South Asian	0.000166	0.000163
Other	0.000328	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: As the sensor component of the NLRP1 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 NLRP1, CASP1, and possibly PYCARD. Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. Activation of NLRP1 inflammasome is also required for HMGB1 secretion. The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death (PubMed:22665479, PubMed:17418785). May be activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, in a NOD2-dependent manner (PubMed:18511561). Contrary to its mouse ortholog, not activated by Bacillus anthracis lethal toxin (PubMed:19651869). It is unclear whether isoform 2 is involved in inflammasome formation. It is not cleaved within the FIIND domain, does not assemble into specks, nor promote IL1B release (PubMed:22665479). However, in an vitro cell-free system, it has been shown to be activated by MDP (PubMed:17349957). Binds ATP (PubMed:11113115, PubMed:15212762). {ECO:0000250|UniProtKB:A1Z198, ECO:0000269|PubMed:11113115, ECO:0000269|PubMed:15212762, ECO:0000269|PubMed:17349957, ECO:0000269|PubMed:17418785, ECO:0000269|PubMed:18511561, ECO:0000269|PubMed:19651869, ECO:0000269|PubMed:22665479, ECO:0000269|PubMed:27662089}.
• Disease: DISEASE: Vitiligo-associated multiple autoimmune disease 1 (VAMAS1) [MIM:606579]: A disorder characterized by the association of vitiligo with several autoimmune and autoinflammatory diseases including autoimmune thyroid disease, rheumatoid arthritis and systemic lupus erythematosus. {ECO:0000269|PubMed:17377159}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Palmoplantar carcinoma, multiple self-healing (MSPC) [MIM:615225]: An autosomal dominant disease characterized by keratopathy with neovascularization, bilateral corneal opacification, palmoplantar hyperkeratosis, dyshidrosis, dystrophic nails, and recurrent keratoacanthomas in palmoplantar skin as well as in conjunctival and corneal epithelia. In addition, patients experience a high susceptibility to malignant squamous cell carcinoma. {ECO:0000269|PubMed:23349227, ECO:0000269|PubMed:27662089}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Autoinflammation with arthritis and dyskeratosis (AIADK) [MIM:617388]: A disorder characterized by recurrent fever, diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Inheritance can be autosomal dominant or autosomal recessive. {ECO:0000269|PubMed:27965258}. Note=The disease may be 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 NLRP1 inflammasome;Inflammasomes;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;Innate Immune System;Immune System;Cellular roles of Anthrax toxin (Consensus)

Intolerance Scores

• loftool: 0.926
• rvis_EVS: 2.71
• rvis_percentile_EVS: 98.94

Haploinsufficiency Scores

• pHI: 0.0625
• hipred: N
• hipred_score: 0.439
• ghis: 0.390

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: Nlrp1a
• 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); 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); hematopoietic system phenotype; liver/biliary system phenotype; respiratory system phenotype; immune system 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); 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: apoptotic process;activation of cysteine-type endopeptidase activity involved in apoptotic process;inflammatory response;viral process;response to muramyl dipeptide;defense response to bacterium;positive regulation of cysteine-type endopeptidase activity involved in apoptotic process;innate immune response;positive regulation of interleukin-1 beta secretion;regulation of inflammatory response;neuron apoptotic process;NLRP1 inflammasome complex assembly
• Cellular component: nucleus;nucleoplasm;cytosol;inflammasome complex;NLRP1 inflammasome complex
• Molecular function: protein binding;ATP binding;cysteine-type endopeptidase activator activity involved in apoptotic process;enzyme binding;protein domain specific binding