TLR3

protein-coding

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

Gene summary

The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta and pancreas, and is restricted to the dendritic subpopulation of the leukocytes. It recognizes dsRNA associated with viral infection, and induces the activation of NF-kappaB and the production of type I interferons. It thus plays a role in host defense against multiple viruses. [provided by RefSeq, Jul 2021]

MANE transcript

NM_003265.3

Inheritance

AD, AR

ClinVar variants

P:1U:401B:168

Top phenotype

Immunodeficiency 83, susceptibility to viral infections

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr4:186,068,911-186,088,073

External References & Databases

Ensembl (ENSG00000164342)

Transcript & Mutation Effects

hg38 • Region Span ~19.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 83, susceptibility to viral infectionsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0800187

Submitter: PanelApp Australia

immunodeficiency 83, susceptibility to viral infectionsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800187

Submitter: PanelApp Australia

immunodeficiency 83, susceptibility to viral infectionsLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0800187

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Immunodeficiency 83, susceptibility to viral infectionsAD/AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals may be susceptible to HSV and other viral infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 17872438; 21911422; 23290562; 25339207; 26513235; 31217193; 32936395

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TLR3 variants in ClinVar

8 Conditions Cataloged

Herpes simplex encephalitis, susceptibility to, 1Total: 525

not specifiedTotal: 130

not providedTotal: 53

TLR3-related disorderTotal: 19

Immunodeficiency 83, susceptibility to viral infectionsTotal: 18

Susceptibility to HIV infectionTotal: 5

Multisystem inflammatory syndrome in childrenTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003265.3. 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			3 clinvar	149 clinvar	2 clinvar	154
missense			361 clinvar	13 clinvar	4 clinvar	378
nonsense		1 clinvar	16 clinvar			17
start loss			1 clinvar			1
frameshift			19 clinvar			19
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	1	401	162	6	570

Highest pathogenic variant AF is 0.00001363291

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003265.3	RefSeq	NP_003256.1	4	MANE Select
ENST00000296795.8	Ensembl	ENSP00000296795.3	4	MANE Select
ENST00000504367.1	Ensembl	ENSP00000423684.1	2	Standard
ENST00000504367.2	Ensembl	ENSP00000423684.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

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

Molecular Function

double-stranded RNA binding
transmembrane signaling receptor activity
protein binding
signaling receptor activity
identical protein binding

Cellular Component

Golgi membrane
extracellular space
cytoplasm
lysosomal membrane
early endosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296795
Coding exons: 4
Length: 18918
Individuals with no LoFs: 125682
Homozygous LoFs: 0
Heterozygous LoFs: 66
Defined: 125748
p: 0.000262

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.514	427	458	0.932	0.0000229	6006
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00071	0.00071	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00020	0.00020	rare
South Asian	0.00056	0.00056	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.533

Intolerance Scores

LoFtool: 0.780
RVIS EVS: -0.24
RVIS percentile EVS: 36.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.475

Gene Damage Prediction

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