TOLLIP

protein-coding

toll interacting protein, the group of C2 domain containing

Gene summary

This gene encodes a ubiquitin-binding protein that interacts with several Toll-like receptor (TLR) signaling cascade components. The encoded protein regulates inflammatory signaling and is involved in interleukin-1 receptor trafficking and in the turnover of IL1R-associated kinase. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

MANE transcript

NM_019009.4

Inheritance

—

ClinVar variants

U:44B:3

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr11:1,274,371-1,309,654

External References & Databases

Ensembl (ENSG00000078902)

Transcript & Mutation Effects

hg38 • Region Span ~35.3 kb

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GenCC 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 TOLLIP variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 40

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019009.4. 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				1 clinvar		1
missense			39 clinvar	1 clinvar	1 clinvar	41
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	0	44	2	1	47

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019009.4	RefSeq	NP_061882.2	6	MANE Select
ENST00000317204.11	Ensembl	ENSP00000314733.5	6	MANE Select
NM_001318512.2	RefSeq	NP_001305441.1	5	Standard
NM_001318514.2	RefSeq	NP_001305443.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tollip	Danio rerio	Structure: caudal fin Quality: curved abnormal

Gene / Model

Organism

Observed Phenotype

tollip

Danio rerio

Structure: caudal fin

Quality: curved

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Toll-like receptor signaling pathway - Homo sapiens (human)
Regulation of toll-like receptor signaling pathway
Apoptosis Modulation and Signaling
IL-1 signaling pathway
Structural Pathway of Interleukin 1 (IL-1)

Biological Process

ubiquitin-dependent protein catabolic process
autophagy
inflammatory response
signal transduction
cell-cell signaling

Molecular Function

interleukin-1, type I receptor binding
protein binding
kinase binding
ubiquitin conjugating enzyme binding
ubiquitin protein ligase binding

Cellular Component

extracellular region
cytoplasm
cytosol
nuclear body
azurophil granule lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000317204
Coding exons: 6
Length: 35284
Individuals with no LoFs: 125678
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125688
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.12	142	185	0.769	0.0000126	1776
Missense (PolyPhen)		40	68.346	0.58526		600
Synonymous	0.429	77	81.9	0.940	0.00000647	542
Loss of Function	2.27	4	12.7	0.314	6.32e-7	133

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.000046	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the signaling pathway of IL-1 and Toll-like receptors. Inhibits cell activation by microbial products. Recruits IRAK1 to the IL-1 receptor complex. Inhibits IRAK1 phosphorylation and kinase activity (PubMed:11751856). Connects the ubiquitin pathway to autophagy by functioning as a ubiquitin- ATG8 family adapter and thus mediating autophagic clearance of ubiquitin conjugates. The TOLLIP-dependent selective autophagy pathway plays an important role in clearance of cytotoxic polyQ proteins aggregates (PubMed:25042851). {ECO:0000269|PubMed:11751856, ECO:0000269|PubMed:25042851}.;

Recessive Scores

pRec: 0.144

Intolerance Scores

LoFtool: 0.200
RVIS EVS: -0.47
RVIS percentile EVS: 23.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.792

Gene Damage Prediction

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