NLRC4

protein-coding

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

Gene summary

This gene encodes a member of the caspase recruitment domain-containing NLR family. Family members play essential roles in innate immune response to a wide range of pathogenic organisms, tissue damage and other cellular stresses. Mutations in this gene result in autoinflammation with infantile enterocolitis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

Previous symbols:

CARD12

MANE transcript

NM_001199138.2

Inheritance

ClinVar variants

P:15U:547B:263

Top phenotype

Autoinflammation with infantile enterocolitis (AIFEC); Familial cold autoinflammatory syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr2:32,224,453-32,265,732

External References & Databases

Ensembl (ENSG00000091106)

Transcript & Mutation Effects

hg38 • Region Span ~41.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

periodic fever-infantile enterocolitis-autoinflammatory syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014472

Submitter: Labcorp Genetics (formerly Invitae)

periodic fever-infantile enterocolitis-autoinflammatory syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014472

Submitter: PanelApp Australia

familial cold autoinflammatory syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014498

Submitter: Labcorp Genetics (formerly Invitae)

periodic fever-infantile enterocolitis-autoinflammatory syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014472

Submitter: Illumina

The NLRC4 gene is located on chromosome 2 at 2p22.3 and encodes the NLR family CARD domain containing 4 protein. As a key component of the NLRC4 inflammasome, this protein plays an important role in innate immune responses. NLRC4 oligomerization triggers inflammasome assembly and activation, which leads to the activation of caspase-1, production of cytokines such as IL-1β and IL18, and inflammatory cell death, or pyroptosis. NLRC4 was first reported in relation to autosomal dominant NCRL4 related autoinflammatory syndrome in 2014 (25217960: Romberg et al. 201; 25217959: Canna et al. 2014). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. At least five missense variants have been identified in a heterozygous state in six affected cases (25217960: Romberg et al. 2014; 25217959: Canna et al. 2014; 25385754: Kitamura et al. 2014; 27203668: Volker-Touw et al. 2017; 29778503: Moghaddas et al. 2018). In four affected individuals NLRC4 variants occurred de novo, in two families the NLRC4 variant segregated with disease. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Data examining the impact of pathogenic variants on NLRC4 function, provide evidence for a gain of function mechanism of disease (25217960: Romberg et al. 2014; 25217959: Canna et al. 2014; 25385754: Kitamura et al. 2014). The gene-disease relationship is also supported by a knock-in mouse model which recapitulates the human phenotype (25385754: Kitamura et al. 2014). In summary, NLRC4 is definitively associated with autosomal dominant NCRL4 related autoinflammatory syndrome. Lumping and splitting considerations: OMIM 616115: Familial cold autoinflammatory syndrome 4; OMIM 616050:Autoinflammation with infantile enterocolitis. According to the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern and the above disorders were ‘lumped’ into the term NLRC4-associated autoinflammatory disease. Duncan and Canna (2018; PMID 29247997) describe the spectrum of NLRC4-associated autoinflammatory diseases and highlight that not all patients with NLRC4 inflammasomopathy develop macrophage activation syndrome (MAS) or enterocolitis. All variants described to date in association with this spectrum of disorders have been heterozygous gain-of-function variants, indicating no difference in inheritance pattern or disease mechanism. Although a small number of patients have been described, the possibility of genotype/phenotype correlation based on variant location has been proposed.

periodic fever-infantile enterocolitis-autoinflammatory syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014472

Submitter: Orphanet

Clinical Genomic Database (CGD)

Autoinflammation with infantile enterocolitis (AIFEC); Familial cold autoinflammatory syndrome 4AD

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: 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

Refs: 25217959; 25217960; 25385754

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NLRC4 variants in ClinVar

10 Conditions Cataloged

Periodic fever-infantile enterocolitis-autoinflammatory syndromeTotal: 779

Familial cold autoinflammatory syndrome 4Total: 778

not providedTotal: 163

Inborn genetic diseasesTotal: 111

not specifiedTotal: 92

Autoinflammatory syndromeTotal: 69

NLRC4-related disorderTotal: 35

Syndrome of entercolitis and autoinflmmation caused by mutation of NLRC4 (SCAN4)Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001199138.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	202 clinvar	4 clinvar	216
missense	6 clinvar	7 clinvar	489 clinvar	40 clinvar	1 clinvar	543
nonsense		1 clinvar	16 clinvar	3 clinvar		20
start loss						0
frameshift		1 clinvar	25 clinvar	12 clinvar		38
splice donor/acceptor (+/-2bp)			7 clinvar	1 clinvar		8
Total	6	9	547	258	5	825

Highest pathogenic variant AF is 0.0000020521604

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001199138.2	RefSeq	NP_001186067.1	8	MANE Select
ENST00000402280.6	Ensembl	ENSP00000385428.1	8	MANE Select
NM_001199139.1	RefSeq	NP_001186068.1	8	Standard
NM_001302504.1	RefSeq	NP_001289433.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

activation of innate immune response
apoptotic process
activation of cysteine-type endopeptidase activity involved in apoptotic process
inflammatory response
detection of bacterium

Molecular Function

magnesium ion binding
protein binding
ATP binding
identical protein binding
protein homodimerization activity

Cellular Component

cytosol
IPAF inflammasome complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000404025
Coding exons: 8
Length: 41402
Individuals with no LoFs: 125526
Homozygous LoFs: 1
Heterozygous LoFs: 221
Defined: 125748
p: 0.000883

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.977	476	540	0.882	0.0000276	6828
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0015	0.0015	notable
Latino/Admixed American	0.00084	0.00084	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0016	0.0016	notable
Finnish	0.0012	0.0012	notable
European (Non-Finnish)	0.00089	0.00089	rare
South Asian	0.00040	0.00039	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.321

Intolerance Scores

LoFtool: 0.850
RVIS EVS: -0.6
RVIS percentile EVS: 18.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.523

Gene Damage Prediction

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