NLRC4

NLR family CARD domain containing 4, the group of NLR family|Caspase recruitment domain containing

Basic information

Region (hg38): 2:32224453-32265732

Previous symbols: [ "CARD12" ]

Links

ENSG00000091106

∙ NCBI:58484 ∙ OMIM:606831 ∙ HGNC:16412 ∙ Uniprot:Q9NPP4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

periodic fever-infantile enterocolitis-autoinflammatory syndrome (Definitive), mode of inheritance: AD
periodic fever-infantile enterocolitis-autoinflammatory syndrome (Supportive), mode of inheritance: AD
periodic fever-infantile enterocolitis-autoinflammatory syndrome (Strong), mode of inheritance: AD
familial cold autoinflammatory syndrome 4 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Autoinflammation with infantile enterocolitis (AIFEC); Familial cold autoinflammatory syndrome 4	AD	Allergy/Immunology/Infectious	In Autoinflammation with infantile enterocolitis, individuals present with recurrent autoinflammatory manifestations in infancy, and treatment with IL1R antagonists has been described as beneficial (decreased frequency of flares, corticosteroid requirements, and clinical and lab severity); In Familial cold autoinflammatory syndrome 4, manifestations frequently resolve without treatments, though analgesics may be helpful related to joint pain	Allergy/Immunology/Infectious	25217959; 25217960; 25385754

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NLRC4 gene.

Periodic_fever-infantile_enterocolitis-autoinflammatory_syndrome (702 variants)
Familial_cold_autoinflammatory_syndrome_4 (702 variants)
not_provided (104 variants)
Inborn_genetic_diseases (89 variants)
Autoinflammatory_syndrome (69 variants)
NLRC4-related_disorder (24 variants)
not_specified (19 variants)
Syndrome_of_entercolitis_and_autoinflmmation_caused_by_mutation_of_NLRC4_(SCAN4) (1 variants)
Atopic_eczema (1 variants)
See_cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NLRC4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001199138.2. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	173 clinvar	5 clinvar	188
missense	6 clinvar	7 clinvar	435 clinvar	26 clinvar	4 clinvar	478
nonsense		1 clinvar	12 clinvar	3 clinvar		16
start loss						0
frameshift		1 clinvar	24 clinvar	9 clinvar		34
splice donor/acceptor (+/-2bp)			5 clinvar	1 clinvar		6
Total	6	9	486	212	9

Highest pathogenic variant AF is 0.00000205216

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NLRC4	protein_coding	protein_coding	ENST00000404025	8	41402

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
9.87e-12	0.898	125526	1	221	125748	0.000883

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.977	476	540	0.882	0.0000276	6828
Missense in Polyphen		98	134.13	0.73064		1904
Synonymous	-0.0576	213	212	1.00	0.0000113	1948
Loss of Function	1.94	23	35.5	0.648	0.00000185	454

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00233	0.00232
Ashkenazi Jewish	0.00	0.00
East Asian	0.00163	0.00163
Finnish	0.00120	0.00116
European (Non-Finnish)	0.000892	0.000888
Middle Eastern	0.00163	0.00163
South Asian	0.000401	0.000392
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

Function: FUNCTION: Key component of inflammasomes that indirectly senses specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis (PubMed:15107016). The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria (By similarity). {ECO:0000250|UniProtKB:Q3UP24, ECO:0000269|PubMed:15107016}.;
Disease: DISEASE: Autoinflammation with infantile enterocolitis (AIFEC) [MIM:616050]: An autosomal dominant disorder characterized by neonatal-onset enterocolitis, periodic fever, and fatal or near- fatal episodes of autoinflammation. Affected individuals tend to have poor overall growth and gastrointestinal symptoms in infancy, recurrent febrile episodes with splenomegaly, and sometimes hematologic disturbances, arthralgias, or myalgias. {ECO:0000269|PubMed:25217959, ECO:0000269|PubMed:25217960}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Familial cold autoinflammatory syndrome 4 (FCAS4) [MIM:616115]: A form of autoinflammatory syndrome, a rare autosomal dominant systemic 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. {ECO:0000269|PubMed:25385754}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Salmonella infection - Homo sapiens (human);Legionellosis - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);Nucleotide-binding Oligomerization Domain (NOD) pathway;TP53 Regulates Transcription of Cell Death Genes;Gene expression (Transcription);Generic Transcription Pathway;Inflammasomes;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;TP53 Regulates Transcription of Cell Death Genes;RNA Polymerase II Transcription;Innate Immune System;Immune System;TP53 Regulates Transcription of Caspase Activators and Caspases;Transcriptional Regulation by TP53;Direct p53 effectors;The IPAF inflammasome (Consensus)

Recessive Scores

pRec: 0.321

Intolerance Scores

loftool: 0.850
rvis_EVS: -0.6
rvis_percentile_EVS: 18.21

Haploinsufficiency Scores

pHI: 0.124
hipred: N
hipred_score: 0.441
ghis: 0.510

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.523

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Nlrc4
Phenotype: cellular phenotype; hematopoietic system phenotype; immune system phenotype;

Gene ontology

Biological process: activation of innate immune response;apoptotic process;activation of cysteine-type endopeptidase activity involved in apoptotic process;inflammatory response;detection of bacterium;defense response to bacterium;regulation of apoptotic process;positive regulation of apoptotic process;innate immune response;interleukin-1 beta secretion;positive regulation of NF-kappaB transcription factor activity;protein homooligomerization;pyroptosis
Cellular component: cytosol;IPAF inflammasome complex
Molecular function: magnesium ion binding;protein binding;ATP binding;identical protein binding;protein homodimerization activity