TICAM1

protein-coding

TIR domain containing adaptor molecule 1, the group of TIR domain containing

Gene summary

This gene encodes an adaptor protein containing a Toll/interleukin-1 receptor (TIR) homology domain, which is an intracellular signaling domain that mediates protein-protein interactions between the Toll-like receptors (TLRs) and signal-transduction components. This protein is involved in native immunity against invading pathogens. It specifically interacts with toll-like receptor 3, but not with other TLRs, and this association mediates dsRNA induction of interferon-beta through activation of nuclear factor kappa-B, during an antiviral immune response. Mutations in this gene are associated with encephalopathy, acute, infection-induced. [provided by RefSeq, Jul 2020]

MANE transcript

NM_182919.4

Inheritance

AR, AD, SD

ClinVar variants

U:232B:201

Top phenotype

Encephalopathy, acute, infection-induceed (herpes-specific), susceptibility to, 6

gnomAD constraint

pLI —, LoF o/e —

Max pathogenic AF

—

Genomic locus

chr19:4,815,932-4,831,712

External References & Databases

Ensembl (ENSG00000127666)

Transcript & Mutation Effects

hg38 • Region Span ~15.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013921

Submitter: PanelApp Australia

encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013921

Submitter: Labcorp Genetics (formerly Invitae)

encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013921

Submitter: Labcorp Genetics (formerly Invitae)

encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 6LIMITED

Inheritance Pattern: SD

Disease ID:MONDO:0013921

Submitter: Ambry Genetics

encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013921

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Encephalopathy, acute, infection-induceed (herpes-specific), susceptibility to, 6AD/AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals may be susceptible to severe herpes simplex virus infections (eg, herpes encephalitis), and awareness may allow early diagnosis and treatment (eg, with acyclovir, which has been reported as effective reported individuals), potentially decreasing morbidity and mortality

Refs: 22105173

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TICAM1 variants in ClinVar

5 Conditions Cataloged

Herpes simplex encephalitis, susceptibility to, 4Total: 392

not specifiedTotal: 121

not providedTotal: 26

TICAM1-related disorderTotal: 16

Susceptibility to severe COVID-19Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182919.4. 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				173 clinvar	1 clinvar	174
missense			225 clinvar	25 clinvar	2 clinvar	252
nonsense			4 clinvar			4
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)						0
Total	0	0	232	198	3	433

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_182919.4	RefSeq	NP_891549.1	1	MANE Select
ENST00000248244.6	Ensembl	ENSP00000248244.4	1	MANE Select
NM_001385678.1	RefSeq	NP_001372607.1	2	Standard
NM_001385679.1	RefSeq	NP_001372608.1	1	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)
Pertussis - Homo sapiens (human)
Influenza A - Homo sapiens (human)
Chagas disease (American trypanosomiasis) - Homo sapiens (human)
Necroptosis - Homo sapiens (human)

Biological Process

macrophage activation involved in immune response
positive regulation of myeloid dendritic cell cytokine production
MyD88-independent toll-like receptor signaling pathway
inflammatory response
I-kappaB kinase/NF-kappaB signaling

Molecular Function

protein binding
protein kinase binding

Cellular Component

mitochondrion
autophagosome
cytosol
endosome membrane
ripoptosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000248244
Coding exons: 1
Length: 15773

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.718	400	443	0.904	0.0000270	4534
Missense (PolyPhen)		67	92.173	0.72689		1013
Synonymous	-0.267	210	205	1.02	0.0000142	1570
Loss of Function

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in innate immunity against invading pathogens. Adapter used by TLR3 and TLR4 (through TICAM2) to mediate NF- kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis. Ligand binding to these receptors results in TRIF recruitment through its TIR domain. Distinct protein- interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively. Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of proinflammatory cytokines (By similarity). {ECO:0000250|UniProtKB:Q80UF7, ECO:0000269|PubMed:12471095, ECO:0000269|PubMed:12539043, ECO:0000269|PubMed:14739303}.;
Disease: DISEASE: Encephalopathy, acute, infection-induced, Herpes- specific, 6 (IIAE6) [MIM:614850]: 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:22105173}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.141

Intolerance Scores

LoFtool: 0.350
RVIS EVS: -0.15
RVIS percentile EVS: 42.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.613

Gene Damage Prediction

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