TLR4
toll like receptor 4, the group of CD molecules|Toll like receptors
Basic information
Region (hg38): 9:117704174-117724735
Links
Phenotypes
GenCC
Source:
No genCC data.
ClinVar
This is a list of variants' phenotypes submitted to
- Inborn genetic diseases (19 variants)
- not provided (10 variants)
- Lung adenocarcinoma (4 variants)
- Hereditary angioedema with normal C1Inh (1 variants)
- Squamous cell carcinoma (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the TLR4 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 | 8 | |||||
| missense | 20 | 20 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| inframe indel | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| splice region ? | 0 | |||||
| non coding ? | 5 | |||||
| Total | 0 | 0 | 22 | 7 | 4 |
Variants in TLR4
This is a list of pathogenic ClinVar variants found in the TLR4 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 9-117704478-G-T | Lung adenocarcinoma | Uncertain significance (Jun 06, 2022) | ||
| 9-117704494-G-T | not specified | Uncertain significance (Jul 25, 2023) | ||
| 9-117704533-G-A | not specified | Uncertain significance (Mar 23, 2022) | ||
| 9-117704536-A-G | not specified | Uncertain significance (May 18, 2022) | ||
| 9-117708644-C-G | not specified | Uncertain significance (Nov 21, 2022) | ||
| 9-117708651-T-G | Uncertain significance (Mar 01, 2024) | |||
| 9-117708688-C-G | TLR4-related disorder | Benign (Aug 09, 2019) | ||
| 9-117712405-A-G | TLR4-related disorder | Likely benign (Feb 16, 2023) | ||
| 9-117712467-C-T | Benign (Aug 07, 2018) | |||
| 9-117712474-A-G | not specified | Uncertain significance (Jan 02, 2024) | ||
| 9-117712563-C-A | TLR4-related disorder | Benign/Likely benign (Apr 01, 2021) | ||
| 9-117712564-A-G | not specified | Uncertain significance (Jun 26, 2023) | ||
| 9-117712617-A-G | Benign (Aug 16, 2018) | |||
| 9-117712649-TGACCAATCTAGAGCACTTG-T | not specified • Susceptibility to severe COVID-19 | Conflicting classifications of pathogenicity (Jul 01, 2022) | ||
| 9-117712651-A-G | TLR4-related disorder | Likely benign (Jun 08, 2023) | ||
| 9-117712685-A-G | not specified | Uncertain significance (Mar 01, 2023) | ||
| 9-117712735-C-G | not specified | Uncertain significance (Nov 14, 2023) | ||
| 9-117712742-A-T | not specified | Uncertain significance (Sep 22, 2023) | ||
| 9-117712954-G-T | not specified | Uncertain significance (May 27, 2022) | ||
| 9-117712970-G-A | not provided (-) | |||
| 9-117713024-A-G | TLR4 POLYMORPHISM • Pericementitis • Susceptibility to severe coronavirus disease (COVID-19) • COPD, severe early onset | Conflicting classifications of pathogenicity; protective (Sep 01, 2023) | ||
| 9-117713029-A-G | not specified | Uncertain significance (May 23, 2023) | ||
| 9-117713053-A-T | not specified | Uncertain significance (Aug 02, 2021) | ||
| 9-117713143-A-G | not specified | Uncertain significance (Nov 15, 2021) | ||
| 9-117713145-C-A | not specified | Uncertain significance (Oct 07, 2022) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| TLR4 | protein_coding | protein_coding | ENST00000355622 | 3 | 12540 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 4.61e-9 | 0.823 | 125454 | 1 | 256 | 125711 | 0.00102 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 0.647 | 379 | 416 | 0.911 | 0.0000200 | 5553 |
| Missense in Polyphen | 115 | 159.35 | 0.72168 | 2264 | ||
| Synonymous | 0.381 | 158 | 164 | 0.962 | 0.00000792 | 1618 |
| Loss of Function | 1.59 | 17 | 25.7 | 0.661 | 0.00000137 | 328 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000902 | 0.000902 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00120 | 0.00120 |
| Finnish | 0.000139 | 0.000139 |
| European (Non-Finnish) | 0.000186 | 0.000185 |
| Middle Eastern | 0.00120 | 0.00120 |
| South Asian | 0.00575 | 0.00573 |
| Other | 0.000984 | 0.000978 |
dbNSFP
Source:
- Function
- FUNCTION: Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Acts via MYD88, TIRAP and TRAF6, leading to NF- kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634, PubMed:27022195). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression (PubMed:15809303). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid- beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B- dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor (PubMed:16622205). {ECO:0000269|PubMed:10835634, ECO:0000269|PubMed:15809303, ECO:0000269|PubMed:16622205, ECO:0000269|PubMed:17478729, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:20711192, ECO:0000269|PubMed:23880187, ECO:0000269|PubMed:27022195, ECO:0000269|PubMed:9237759}.;
- Pathway
- PI3K-Akt signaling pathway - Homo sapiens (human);Pertussis - Homo sapiens (human);Salmonella infection - Homo sapiens (human);Legionellosis - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Influenza A - Homo sapiens (human);Inflammatory bowel disease (IBD) - Homo sapiens (human);Phagosome - Homo sapiens (human);Amoebiasis - Homo sapiens (human);Malaria - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Necroptosis - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);Tuberculosis - Homo sapiens (human);Leishmaniasis - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Pathogenic Escherichia coli infection - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Measles - Homo sapiens (human);Rheumatoid arthritis - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Regulation of toll-like receptor signaling pathway;Pathogenic Escherichia coli infection;Corticotropin-releasing hormone signaling pathway;Spinal Cord Injury;Primary Focal Segmental Glomerulosclerosis FSGS;TLR4 Signaling and Tolerance;Toll-like Receptor Signaling;Simplified Depiction of MYD88 Distinct Input-Output Pathway;Nanomaterial induced inflammasome activation;ApoE and miR-146 in inflammation and atherosclerosis;Fibrin Complement Receptor 3 Signaling Pathway;PI3K-Akt Signaling Pathway;Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;Toll-like Receptor Signaling Pathway;TLR NFkB;nf-kb signaling pathway;toll-like receptor pathway;Toll-Like Receptors Cascades;Ligand-dependent caspase activation;Caspase activation via extrinsic apoptotic signalling pathway;Innate Immune System;Immune System;Apoptosis;Programmed Cell Death;Adaptive Immune System;inactivation of gsk3 by akt causes accumulation of b-catenin in alveolar macrophages;Antigen processing-Cross presentation;Class I MHC mediated antigen processing & presentation;TLR p38;Regulation of TLR by endogenous ligand;ER-Phagosome pathway;TLR ECSIT MEKK1 JNK;TLR ECSIT MEKK1 p38;TLR JNK;Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon;IKK complex recruitment mediated by RIP1;TRIF-mediated programmed cell death;TRAF6-mediated induction of TAK1 complex within TLR4 complex;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;Endogenous TLR signaling
(Consensus)
Recessive Scores
- pRec
- 0.920
Intolerance Scores
- loftool
- 0.846
- rvis_EVS
- -0.02
- rvis_percentile_EVS
- 52.32
Haploinsufficiency Scores
- pHI
- 0.217
- hipred
- N
- hipred_score
- 0.428
- ghis
- 0.468
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Tlr4
- Phenotype
- muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); normal phenotype; 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); 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; growth/size/body region phenotype; vision/eye phenotype; limbs/digits/tail 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); digestive/alimentary phenotype; skeleton phenotype; renal/urinary system phenotype; immune system phenotype; liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); neoplasm; pigmentation phenotype;
Gene ontology
- Biological process
- activation of MAPK activity;toll-like receptor signaling pathway;B cell proliferation involved in immune response;nitric oxide production involved in inflammatory response;regulation of dendritic cell cytokine production;MyD88-dependent toll-like receptor signaling pathway;MyD88-independent toll-like receptor signaling pathway;inflammatory response;immune response;I-kappaB kinase/NF-kappaB signaling;I-kappaB phosphorylation;positive regulation of platelet activation;positive regulation of gene expression;astrocyte development;detection of fungus;positive regulation of B cell proliferation;lipopolysaccharide-mediated signaling pathway;response to lipopolysaccharide;detection of lipopolysaccharide;interferon-gamma production;negative regulation of interferon-gamma production;negative regulation of interleukin-17 production;negative regulation of interleukin-23 production;negative regulation of interleukin-6 production;negative regulation of tumor necrosis factor production;positive regulation of chemokine production;positive regulation of interferon-alpha production;positive regulation of interferon-beta production;positive regulation of interferon-gamma production;positive regulation of interleukin-1 production;positive regulation of interleukin-10 production;positive regulation of interleukin-12 production;positive regulation of interleukin-6 production;positive regulation of interleukin-8 production;positive regulation of tumor necrosis factor production;negative regulation of MyD88-independent toll-like receptor signaling pathway;toll-like receptor 4 signaling pathway;TRIF-dependent toll-like receptor signaling pathway;T-helper 1 type immune response;macrophage activation;positive regulation of tumor necrosis factor biosynthetic process;defense response to bacterium;positive regulation of macrophage activation;positive regulation of I-kappaB kinase/NF-kappaB signaling;positive regulation of interleukin-12 biosynthetic process;innate immune response;positive regulation of MHC class II biosynthetic process;positive regulation of interferon-beta biosynthetic process;positive regulation of interleukin-8 biosynthetic process;positive regulation of nitric oxide biosynthetic process;negative regulation of osteoclast differentiation;positive regulation of transcription by RNA polymerase II;positive regulation of JNK cascade;interleukin-1 beta secretion;positive regulation of interleukin-1 beta secretion;positive regulation of inflammatory response;defense response to Gram-negative bacterium;positive regulation of NF-kappaB transcription factor activity;positive regulation of nitric-oxide synthase biosynthetic process;intestinal epithelial structure maintenance;positive regulation of macrophage cytokine production;necroptotic process;negative regulation of ERK1 and ERK2 cascade;positive regulation of ERK1 and ERK2 cascade;positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway;positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway;cellular response to lipopolysaccharide;cellular response to lipoteichoic acid;cellular response to mechanical stimulus;cellular response to interferon-gamma;apoptotic signaling pathway;negative regulation of cold-induced thermogenesis;cellular response to oxidised low-density lipoprotein particle stimulus;positive regulation of cytokine production involved in inflammatory response;positive regulation of NLRP3 inflammasome complex assembly;positive regulation of NIK/NF-kappaB signaling;positive regulation of oxidative stress-induced neuron death;positive regulation of reactive oxygen species biosynthetic process;positive regulation of cellular response to macrophage colony-stimulating factor stimulus;cellular response to amyloid-beta
- Cellular component
- cytoplasm;early endosome;plasma membrane;integral component of plasma membrane;external side of plasma membrane;cell surface;endosome membrane;intrinsic component of plasma membrane;receptor complex;lipopolysaccharide receptor complex;perinuclear region of cytoplasm
- Molecular function
- lipopolysaccharide binding;amyloid-beta binding;lipopolysaccharide receptor activity;transmembrane signaling receptor activity;signaling receptor binding;protein binding;signaling receptor activity;identical protein binding;protein heterodimerization activity