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 (4 variants)
• Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4 (3 variants)
• not provided (2 variants)
• Syndrome of entercolitis and autoinflmmation caused by mutation of NLRC4 (SCAN4) (1 variants)
• Familial cold autoinflammatory syndrome 4 (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.

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	144	5	158
missense	5	5	376	10	5	401
nonsense		1	10	2		13
start loss						0
frameshift			24	4		28
inframe indel			5			5
splice donor/acceptor (+/-2bp)			1	1		2
splice region			11	13	1	25
non coding			1	38	15	54
Total	5	6	426	199	25

Variants in NLRC4

This is a list of pathogenic ClinVar variants found in the NLRC4 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-32224460-G-C		not specified	Uncertain significance (Jul 22, 2024)
2-32224478-C-T		Familial cold autoinflammatory syndrome 4;Periodic fever-infantile enterocolitis-autoinflammatory syndrome	Uncertain significance (Aug 16, 2023)
2-32224484-C-G		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4	Uncertain significance (Jan 28, 2023)
2-32224486-A-T		Familial cold autoinflammatory syndrome 4;Periodic fever-infantile enterocolitis-autoinflammatory syndrome • Inborn genetic diseases	Uncertain significance (Dec 22, 2023)
2-32224495-G-C		Familial cold autoinflammatory syndrome 4;Periodic fever-infantile enterocolitis-autoinflammatory syndrome	Uncertain significance (Dec 15, 2018)
2-32224496-C-T		Familial cold autoinflammatory syndrome 4;Periodic fever-infantile enterocolitis-autoinflammatory syndrome	Uncertain significance (Nov 27, 2017)
2-32224515-A-C		Familial cold autoinflammatory syndrome 4;Periodic fever-infantile enterocolitis-autoinflammatory syndrome	Likely benign (Jul 07, 2023)
2-32224522-T-C		Familial cold autoinflammatory syndrome 4;Periodic fever-infantile enterocolitis-autoinflammatory syndrome	Uncertain significance (Aug 22, 2023)
2-32224523-C-A		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4 • Inborn genetic diseases	Uncertain significance (May 30, 2023)
2-32224544-G-A		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4	Uncertain significance (Jul 24, 2021)
2-32224544-G-T		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4	Uncertain significance (Oct 16, 2023)
2-32224578-C-T		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4	Likely benign (May 28, 2021)
2-32224580-C-T		Familial cold autoinflammatory syndrome 4;Periodic fever-infantile enterocolitis-autoinflammatory syndrome	Uncertain significance (Dec 06, 2023)
2-32224589-G-A		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4	Uncertain significance (Apr 28, 2019)
2-32224591-T-C		Autoinflammatory syndrome • Familial cold autoinflammatory syndrome 4;Periodic fever-infantile enterocolitis-autoinflammatory syndrome	Conflicting classifications of pathogenicity (Dec 23, 2023)
2-32224597-A-G		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4	Uncertain significance (Aug 26, 2018)
2-32224599-T-G		NLRC4-related disorder	Uncertain significance (Jan 31, 2024)
2-32224603-G-A			Likely benign (Jul 01, 2023)
2-32224603-G-C		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4 • Autoinflammatory syndrome • NLRC4-related disorder	Likely benign (Dec 02, 2023)
2-32224603-G-T		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4	Uncertain significance (Feb 17, 2020)
2-32224609-T-A		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4	Uncertain significance (Oct 13, 2023)
2-32224610-C-G		Familial cold autoinflammatory syndrome 4;Periodic fever-infantile enterocolitis-autoinflammatory syndrome	Uncertain significance (Dec 19, 2020)
2-32224621-T-C		Familial cold autoinflammatory syndrome 4;Periodic fever-infantile enterocolitis-autoinflammatory syndrome	Uncertain significance (Jan 09, 2023)
2-32224623-T-G		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4 • Inborn genetic diseases	Uncertain significance (May 11, 2023)
2-32224624-T-C		Periodic fever-infantile enterocolitis-autoinflammatory syndrome;Familial cold autoinflammatory syndrome 4	Uncertain significance (Jul 25, 2022)

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