IL10RA

protein-coding

interleukin 10 receptor subunit alpha, the group of CD molecules|Interleukin receptors

Gene summary

The protein encoded by this gene is a receptor for interleukin 10. This protein is structurally related to interferon receptors. It has been shown to mediate the immunosuppressive signal of interleukin 10, and thus inhibits the synthesis of proinflammatory cytokines. This receptor is reported to promote survival of progenitor myeloid cells through the insulin receptor substrate-2/PI 3-kinase/AKT pathway. Activation of this receptor leads to tyrosine phosphorylation of JAK1 and TYK2 kinases. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Jan 2009]

Previous symbols:

IL10R

MANE transcript

NM_001558.4

Inheritance

ClinVar variants

P:29U:195B:167

Top phenotype

Inflammatory bowel disease 28, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr11:117,986,370-118,003,037

External References & Databases

Ensembl (ENSG00000110324)

Transcript & Mutation Effects

hg38 • Region Span ~16.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

inflammatory bowel disease 28DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013153

Submitter: ClinGen

The IL10RA gene encodes for IL10Rα. IL10Rα is the ligand binding subunit of the IL10R receptor complex in hematopoietic cells. L10 signaling functions as an anti-inflammatory pathway that can inhibit proinflammatory responses of both innate and adaptive immune cells. Inflammatory bowel disease 28, early onset, autosomal recessive (MONDO: 0013153) presents as very onset IBD. A total of 22 variants, including nonsense and missense, have been reported in 11 patients in 4 publications (PMID: 19890111, 25373860, 23158016, 28267044). Variants were found to be inherited in an autosomal recessive manner, variants segregate with disease, and the disease mechanism is suggested to be loss of function. Experimental evidence includes reduction of IL10RB expression and IL10 signaling in the patients’ cells and loss of Il-10 response in LPS stimulated PBMCs. Cells carrying the IL10RA G141R mutation secreted increased levels of TNF- α; TGF-β1; interleukin-1 α, -1β, -2, and -6; soluble receptor of interleukin-6. IL10R−/− mice. Animals develop a disease that appears largely to depend upon an inappropriate immune response to intestinal antigens, and recapitulate human disease. Reports included in the curation span the time period from 2009 until present, therefore the classification is definitive.

inflammatory bowel disease 28STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013153

Submitter: Labcorp Genetics (formerly Invitae)

IL10-related early-onset inflammatory bowel diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016542

Submitter: Orphanet

inflammatory bowel disease 28MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013153

Submitter: Ambry Genetics

inflammatory bowel disease 28STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013153

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Inflammatory bowel disease 28, autosomal recessiveAR

Manifestation: Allergy/Immunology/Infectious; Gastrointestinal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 19890111; 21519361; 22476154

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IL10RA variants in ClinVar

5 Conditions Cataloged

Inflammatory bowel disease 28Total: 403

Inborn genetic diseasesTotal: 66

not providedTotal: 59

not specifiedTotal: 58

IL10RA-related disorderTotal: 18

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001558.4. 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	4 clinvar	143 clinvar	1 clinvar	149
missense	6 clinvar	4 clinvar	187 clinvar	23 clinvar		220
nonsense	5 clinvar	2 clinvar	1 clinvar			8
start loss	2 clinvar	1 clinvar				3
frameshift	3 clinvar	1 clinvar				4
splice donor/acceptor (+/-2bp)		4 clinvar	3 clinvar			7
Total	16	13	195	166	1	391

Highest pathogenic variant AF is 0.0010996282

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001558.4	RefSeq	NP_001549.2	7	MANE Select
ENST00000227752.8	Ensembl	ENSP00000227752.4	7	MANE Select
NM_001440423.1	RefSeq	NP_001427352.1	4	Standard
ENST00000526544.5	Ensembl	ENSP00000435317.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
il10ra	Danio rerio	Structure: response to cytokine Quality: decreased process quality abnormal

Gene / Model

Organism

Observed Phenotype

il10ra

Danio rerio

Structure: response to cytokine

Quality: decreased process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Jak-STAT signaling pathway - Homo sapiens (human)
Tuberculosis - Homo sapiens (human)
Toxoplasmosis - Homo sapiens (human)
Cytokine-cytokine receptor interaction - Homo sapiens (human)
Epstein-Barr virus infection - Homo sapiens (human)

Biological Process

cytokine-mediated signaling pathway
response to lipopolysaccharide
regulation of synapse organization

Molecular Function

cytokine receptor activity
interleukin-10 receptor activity
protein binding
interleukin-10 binding
signaling receptor activity

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000227752
Coding exons: 7
Length: 15134
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125748
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.637	286	318	0.900	0.0000176	3766
Missense (PolyPhen)		47	63.939	0.73507		819
Synonymous	-0.600	144	135	1.07	0.00000760	1194
Loss of Function	2.52	6	17.3	0.347	0.00000102	187

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for IL10; binds IL10 with a high affinity.;

Recessive Scores

pRec: 0.407

Intolerance Scores

LoFtool: 0.137
RVIS EVS: 0.98
RVIS percentile EVS: 90.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.923

Gene Damage Prediction

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