NLRC3
protein-codingNLR family CARD domain containing 3, the group of NLR family
Gene summary
This gene encodes a NOD-like receptor family member. The encoded protein is a cytosolic regulator of innate immunity. This protein directly interacts with stimulator of interferon genes (STING), to prevent its proper trafficking, resulting in disruption of STING-dependent activation of the innate immune response. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~38.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NLRC3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_178844.4. 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 | 7 | 3 | 1 | 11 | ||
| missense | 168 | 17 | 3 | 188 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 177 | 20 | 4 | 201 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_849172.2 | 17 | MANE Select | |
| Ensembl | ENSP00000352039.6 | 17 | MANE Select | |
| Ensembl | ENSP00000323897.9 | 18 | Standard | |
| Ensembl | ENSP00000482989.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- STING mediated induction of host immune responses
- Innate Immune System
- Immune System
- IRF3-mediated induction of type I IFN
- Cytosolic sensors of pathogen-associated DNA
Biological Process
- I-kappaB kinase/NF-kappaB signaling
- negative regulation of phosphatidylinositol 3-kinase signaling
- negative regulation of NF-kappaB transcription factor activity
- negative regulation of interferon-alpha production
- negative regulation of interferon-beta production
Molecular Function
- molecular_function
- protein binding
- ATP binding
- phosphatidylinositol 3-kinase regulatory subunit binding
Cellular Component
- cytoplasm
- microtubule organizing center
- cytosol
- perinuclear region of cytoplasm
gnomAD Constraint
Source:
- Gene type
- polymorphic_pseudogene
- Transcript type
- protein_coding
- Transcript
- ENST00000448023
- Coding exons
- 19
- Length
- 38369
- Individuals with no LoFs
- 124411
- Homozygous LoFs
- 2
- Heterozygous LoFs
- 238
- Defined
- 124651
- p
- 0.000963
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.494 | 705 | 669 | 1.05 | 0.0000425 | 7053 |
| Missense (PolyPhen) | 137 | 130.91 | 1.0465 | 1573 | ||
| Synonymous | -1.24 | 339 | 311 | 1.09 | 0.0000221 | 2351 |
| Loss of Function | 0.288 | 39 | 41.0 | 0.951 | 0.00000190 | 470 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00020 | 0.00019 | rare |
| Latino/Admixed American | 0.0036 | 0.0035 | notable |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00047 | 0.00045 | rare |
| Finnish | 0.00043 | 0.00042 | rare |
| European (Non-Finnish) | 0.00057 | 0.00055 | rare |
| South Asian | 0.0012 | 0.0011 | notable |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Negative regulator of the innate immune response (PubMed:15705585, PubMed:22863753, PubMed:25277106). Attenuates signaling pathways activated by Toll-like receptors (TLRs) and the DNA sensor STING/TMEM173 in response to pathogen-associated molecular patterns, such as intracellular poly(dA:dT), but not poly(I:C), or in response to DNA virus infection, including that of Herpes simplex virus 1 (HSV1) (By similarity) (PubMed:22863753). May affect TLR4 signaling by acting at the level of TRAF6 ubiquitination, decreasing the activating 'Lys-63'- linked ubiquitination and leaving unchanged the degradative 'Lys- 48'-linked ubiquitination (PubMed:22863753). Inhibits the PI3K- AKT-mTOR pathway possibly by directly interacting with the posphatidylinositol 3-kinase regulatory subunit p85 (PIK3R1/PIK3R2) and disrupting the association between PIK3R1/PIK3R2 and the catalytic subunit p110 (PIK3CA/PIK3CB/PIK3CD) and reducing PIK3R1/PIK3R2 activation. Via its regulation of the PI3K-AKT-mTOR pathway, controls cell proliferation, predominantly in intestinal epithelial cells (By similarity). May also affect NOD1- or NOD2-mediated NF-kappa-B activation (PubMed:25277106). Might also affect the inflammatory response by preventing NLRP3 inflammasome formation, CASP1 cleavage and IL1B maturation (PubMed:25277106). {ECO:0000250|UniProtKB:Q5DU56, ECO:0000269|PubMed:15705585, ECO:0000269|PubMed:22863753, ECO:0000269|PubMed:25277106}.;
Recessive Scores
- pRec
- 0.112
Essentials
- Essential (CRISPR2)
- N