IL10

protein-coding

interleukin 10, the group of Interleukins

Gene summary

The protein encoded by this gene is a cytokine produced primarily by monocytes and to a lesser extent by lymphocytes. This cytokine has pleiotropic effects in immunoregulation and inflammation. It down-regulates the expression of Th1 cytokines, MHC class II Ags, and costimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. This cytokine can block NF-kappa B activity, and is involved in the regulation of the JAK-STAT signaling pathway. Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract. Mutations in this gene are associated with an increased susceptibility to HIV-1 infection and rheumatoid arthritis. [provided by RefSeq, May 2020]

MANE transcript

NM_000572.3

Inheritance

AR, AD

ClinVar variants

U:56B:44

Top phenotype

Graft vs. host disease

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr1:206,767,602-206,774,541

External References & Databases

Ensembl (ENSG00000136634)

Transcript & Mutation Effects

hg38 • Region Span ~6.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

IL10-related early-onset inflammatory bowel diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0016542

Submitter: Ambry Genetics

IL10-related early-onset inflammatory bowel diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0016542

Submitter: ClinGen

*IL10*, also known as *CSIF*, was first reported in relation to autosomal recessive early-onset inflammatory bowel disease (IBD) in 2010 (Glocker EO, et al., PMID: 20934598). Individuals reported to date with IL10-associated early-onset IBD have presented with IBD with an onset between 1 month and 5 years of age without additional characteristic features. Three variants (missense) that have been reported in four unrelated probands in three publications (PMIDs: 20934598, 22549091, 29248579) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 8770874, 9312047, 15534372, 1578140, 17137799, 1827484, 22549091, 23158016). IL10 is a well-established anti-inflammatory cytokine (PMID: 1827484, 1578140, 33691712). In vitro experiments have demonstrated that mutant IL10 carrying patient-associated variants displayed impaired suppression of TNFa production by stimulated PBMCs (PMID: 22549091, 23158016). Multiple mouse models of IL10 deficiency, including *IL10*-knockout and CD4-specific *IL10* knockout mice, recapitulate the spontaneous intestinal inflammation in human disease (PMID: 8770874, 15534372). Notably, both IL10Ra and IL10RB, the subunits of the receptor with which IL10 directly interacts (PMID: 9312047), are also associated with early-onset IBD (PMID: 39795980). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

immune system disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0005046

Submitter: PanelApp Australia

systemic lupus erythematosusSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0007915

Submitter: Orphanet

IL10-related early-onset inflammatory bowel diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016542

Submitter: Orphanet

IL10-related early-onset inflammatory bowel diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0016542

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Graft vs. host diseaseAD

Manifestation: General

Intervention: Pharmacogenomic

Rationale: In Graft vs. host disease, variants may have clinical relevance, as specific allele(s) shown to be a marker of favorable outcome following transplantation

Refs: 14657422; 14657427; 20305143

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IL10 variants in ClinVar

7 Conditions Cataloged

Inflammatory bowel diseaseTotal: 123

not specifiedTotal: 16

not providedTotal: 14

IL10-related early-onset inflammatory bowel diseaseTotal: 1

Rheumatoid arthritisTotal: 1

Graft-versus-host disease, susceptibility toTotal: 1

Susceptibility to HIV infectionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000572.3. 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				41 clinvar		41
missense			54 clinvar	3 clinvar		57
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	56	44	0	100

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000572.3	RefSeq	NP_000563.1	5	MANE Select
ENST00000423557.1	Ensembl	ENSP00000412237.1	5	MANE Select
NM_001382624.1	RefSeq	NP_001369553.1	3	Standard
ENST00000471071.2	Ensembl	ENSP00000493073.2	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

T cell receptor signaling pathway - Homo sapiens (human)
Pertussis - Homo sapiens (human)
Allograft rejection - Homo sapiens (human)
Jak-STAT signaling pathway - Homo sapiens (human)
Systemic lupus erythematosus - Homo sapiens (human)

Biological Process

positive regulation of endothelial cell proliferation
response to molecule of bacterial origin
negative regulation of cytokine secretion involved in immune response
negative regulation of chronic inflammatory response to antigenic stimulus
positive regulation of B cell apoptotic process

Molecular Function

cytokine activity
interleukin-10 receptor binding
protein binding
growth factor activity

Cellular Component

extracellular region
extracellular space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000423557
Coding exons: 5
Length: 4893
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125746
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.841	71	93.9	0.756	0.00000492	1188
Missense (PolyPhen)		14	33.425	0.41885		449
Synonymous	-0.0174	36	35.9	1.00	0.00000176	322
Loss of Function	1.49	5	10.1	0.494	6.63e-7	106

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inhibits the synthesis of a number of cytokines, including IFN-gamma, IL-2, IL-3, TNF and GM-CSF produced by activated macrophages and by helper T-cells.;

Recessive Scores

pRec: 0.945

Intolerance Scores

LoFtool: 0.538
RVIS EVS: 0.04
RVIS percentile EVS: 56.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.962

Gene Damage Prediction

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