TLR3

toll like receptor 3, the group of CD molecules|Toll like receptors

Basic information

Region (hg38): 4:186068910-186088073

Links

ENSG00000164342 ∙ NCBI:7098 ∙ OMIM:603029 ∙ HGNC:11849 ∙ Uniprot:O15455 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• immunodeficiency 83, susceptibility to viral infections (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 83, susceptibility to viral infections	AD/AR	Allergy/Immunology/Infectious	Individuals may be susceptible to HSV and other viral infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial	Allergy/Immunology/Infectious	17872438; 21911422; 23290562; 25339207; 26513235; 31217193; 32936395

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TLR3 gene.

• Herpes simplex encephalitis, susceptibility to, 1 (348 variants)
• Inborn genetic diseases (23 variants)
• not provided (14 variants)
• Immunodeficiency 83, susceptibility to viral infections (8 variants)
• not specified (5 variants)
• TLR3-related condition (4 variants)
• Susceptibility to HIV infection;Immunodeficiency 83, susceptibility to viral infections (2 variants)
• Immunodeficiency 83, susceptibility to viral infections;Susceptibility to HIV infection (2 variants)
• Multisystem inflammatory syndrome in children (1 variants)
• Susceptibility to HIV infection (1 variants)
• Cerebral edema (1 variants)
• - (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TLR3 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			5	90	9	104
missense			204	9	5	218
nonsense			7			7
start loss						0
frameshift			10			10
inframe indel			2			2
splice donor/acceptor (+/-2bp)			1			1
splice region			2	3	2	7
non coding			2	12	4	18
Total	0	0	231	111	18

Variants in TLR3

This is a list of pathogenic ClinVar variants found in the TLR3 region.

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

Position	Type	Phenotype	Significance	ClinVar
4-186076613-C-A		Herpes simplex encephalitis, susceptibility to, 1 • not specified	Benign (Jan 29, 2024)
4-186076620-A-G		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Nov 03, 2022)
4-186076630-CTT-C		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Sep 23, 2022)
4-186076636-C-T		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Nov 01, 2022)
4-186076643-C-T		Herpes simplex encephalitis, susceptibility to, 1	Likely benign (Aug 02, 2023)
4-186076651-G-T		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (May 09, 2023)
4-186076652-G-C		Herpes simplex encephalitis, susceptibility to, 1 • not specified	Uncertain significance (Jan 28, 2023)
4-186076652-G-T		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Apr 10, 2022)
4-186076653-G-C		Herpes simplex encephalitis, susceptibility to, 1	Likely benign (Nov 28, 2023)
4-186076657-G-A		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Oct 07, 2022)
4-186076657-G-C		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Jun 08, 2022)
4-186076658-C-A		Herpes simplex encephalitis, susceptibility to, 1	Likely benign (Sep 27, 2019)
4-186076658-C-T		Herpes simplex encephalitis, susceptibility to, 1	Likely benign (Jul 17, 2023)
4-186076663-T-G		Herpes simplex encephalitis, susceptibility to, 1	Likely benign (Jan 08, 2024)
4-186076680-T-C		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Aug 27, 2023)
4-186076685-A-G		Herpes simplex encephalitis, susceptibility to, 1	Likely benign (Jan 22, 2024)
4-186076690-C-T		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Nov 01, 2022)
4-186076691-C-T		Herpes simplex encephalitis, susceptibility to, 1	Likely benign (Mar 22, 2020)
4-186076705-C-T		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Oct 27, 2023)
4-186076708-T-G		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Dec 25, 2023)
4-186076709-T-C		Herpes simplex encephalitis, susceptibility to, 1	Likely benign (Aug 21, 2022)
4-186076722-GCTGACTGCAGCCACCTGAAGTTGA-G		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Jul 19, 2022)
4-186076728-T-C		Herpes simplex encephalitis, susceptibility to, 1	Uncertain significance (Jun 20, 2023)
4-186076757-C-T		Herpes simplex encephalitis, susceptibility to, 1	Likely benign (Jan 31, 2024)
4-186076758-G-A		Herpes simplex encephalitis, susceptibility to, 1 • TLR3-related disorder	Uncertain significance (Jan 26, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TLR3	protein_coding	protein_coding	ENST00000296795	4	18918

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.63e-7	0.992	125682	0	66	125748	0.000262

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.514	427	458	0.932	0.0000229	6006
Missense in Polyphen		114	142.5	0.8		1982
Synonymous	-0.311	188	183	1.03	0.00000960	1725
Loss of Function	2.41	16	30.3	0.527	0.00000171	379

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000518	0.000516
Ashkenazi Jewish	0.00	0.00
East Asian	0.000707	0.000707
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000203	0.000202
Middle Eastern	0.000707	0.000707
South Asian	0.000556	0.000555
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via the adapter TRIF/TICAM1, leading to NF-kappa-B activation, IRF3 nuclear translocation, cytokine secretion and the inflammatory response. {ECO:0000269|PubMed:12471095, ECO:0000269|PubMed:12539043, ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:16144834, ECO:0000269|PubMed:16720699, ECO:0000269|PubMed:16858407, ECO:0000269|PubMed:17178723, ECO:0000269|PubMed:18172197, ECO:0000269|PubMed:22611194}.
• Disease: DISEASE: Encephalopathy, acute, infection-induced, Herpes- specific, 2 (IIAE2) [MIM:613002]: A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. It is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. {ECO:0000269|PubMed:17872438}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. TLR3 mutations predispose otherwise healthy individuals to isolated herpes simplex encephalitis through a mechanism that involves impaired IFNs production and reduced immune defense against viral infection in the central nervous system.
• Pathway: Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Influenza A - Homo sapiens (human);Necroptosis - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Regulation of toll-like receptor signaling pathway;Toll-like Receptor Signaling;Fibrin Complement Receptor 3 Signaling Pathway;Toll-like Receptor Signaling Pathway;toll-like receptor pathway;TICAM1-dependent activation of IRF3/IRF7;TICAM1, RIP1-mediated IKK complex recruitment ;Toll Like Receptor 3 (TLR3) Cascade;ZBP1(DAI) mediated induction of type I IFNs;Trafficking and processing of endosomal TLR;Toll-Like Receptors Cascades;Innate Immune System;Immune System;RIP-mediated NFkB activation via ZBP1;TLR3-mediated TICAM1-dependent programmed cell death;Cytosolic sensors of pathogen-associated DNA ;Endogenous TLR signaling;TICAM1,TRAF6-dependent induction of TAK1 complex (Consensus)

Recessive Scores

• pRec: 0.533

Intolerance Scores

• loftool: 0.780
• rvis_EVS: -0.24
• rvis_percentile_EVS: 36.28

Haploinsufficiency Scores

• pHI: 0.0933
• hipred: Y
• hipred_score: 0.756
• ghis: 0.457

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.475

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tlr3
• 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); immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; neoplasm; 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); reproductive system phenotype; 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; muscle phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: microglial cell activation;toll-like receptor signaling pathway;regulation of dendritic cell cytokine production;MyD88-independent toll-like receptor signaling pathway;hyperosmotic response;signal transduction;I-kappaB kinase/NF-kappaB signaling;activation of NF-kappaB-inducing kinase activity;I-kappaB phosphorylation;male gonad development;detection of virus;positive regulation of gene expression;positive regulation of chemokine production;positive regulation of interferon-beta 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;positive regulation of toll-like receptor signaling pathway;negative regulation of MyD88-independent toll-like receptor signaling pathway;toll-like receptor 3 signaling pathway;positive regulation of type III interferon production;cellular response to interferon-beta;TRIF-dependent toll-like receptor signaling pathway;cellular response to drug;defense response to bacterium;positive regulation of apoptotic process;positive regulation of I-kappaB kinase/NF-kappaB signaling;response to exogenous dsRNA;positive regulation of interferon-gamma biosynthetic process;positive regulation of chemokine biosynthetic process;innate immune response;positive regulation of interferon-alpha biosynthetic process;positive regulation of interferon-beta biosynthetic process;negative regulation of osteoclast differentiation;positive regulation of angiogenesis;positive regulation of transcription by RNA polymerase II;positive regulation of JNK cascade;positive regulation of inflammatory response;positive regulation of NF-kappaB transcription factor activity;defense response to virus;necroptotic process;cellular response to mechanical stimulus;cellular response to interferon-gamma;cellular response to exogenous dsRNA;apoptotic signaling pathway;extrinsic apoptotic signaling pathway;necroptotic signaling pathway;positive regulation of NIK/NF-kappaB signaling
• Cellular component: Golgi membrane;extracellular space;cytoplasm;lysosomal membrane;early endosome;endoplasmic reticulum membrane;integral component of plasma membrane;cell surface;endosome membrane;membrane;extracellular matrix;endolysosome membrane
• Molecular function: double-stranded RNA binding;transmembrane signaling receptor activity;protein binding;signaling receptor activity;identical protein binding