IL6ST

protein-coding

interleukin 6 cytokine family signal transducer, the group of Fibronectin type III domain containing|CD molecules|Interleukin receptors

Gene summary

The protein encoded by this gene is a signal transducer shared by many cytokines, including interleukin 6 (IL6), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and oncostatin M (OSM). This protein functions as a part of the cytokine receptor complex. The activation of this protein is dependent upon the binding of cytokines to their receptors. vIL6, a protein related to IL6 and encoded by the Kaposi sarcoma-associated herpesvirus, can bypass the interleukin 6 receptor (IL6R) and directly activate this protein. Knockout studies in mice suggest that this gene plays a critical role in regulating myocyte apoptosis. Alternatively spliced transcript variants have been described. A related pseudogene has been identified on chromosome 17. [provided by RefSeq, May 2014]

MANE transcript

NM_002184.4

Inheritance

AR, AD

ClinVar variants

P:21U:374B:155

Top phenotype

Hyper-IgE recurrent infection syndrome 4A, autosomal dominant; Immunodeficiency 94 with autoinflammation and dysmorphic facies; Hyper-IgE recurrent infection syndrome 4B, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr5:55,935,095-55,995,022

External References & Databases

Ensembl (ENSG00000134352)

Transcript & Mutation Effects

hg38 • Region Span ~59.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyper-IgE recurrent infection syndrome 4, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032796

Submitter: Labcorp Genetics (formerly Invitae)

Stuve-Wiedemann syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030756

Submitter: PanelApp Australia

hyper-IgE recurrent infection syndrome 4A, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0800131

Submitter: Labcorp Genetics (formerly Invitae)

hyper-IgE recurrent infection syndrome 4A, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0800131

Submitter: PanelApp Australia

hyper-IgE recurrent infection syndrome 4, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032796

Submitter: PanelApp Australia

immunodeficiency 94 with autoinflammation and dysmorphic faciesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030681

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hyper-IgE recurrent infection syndrome 4A, autosomal dominant; Immunodeficiency 94 with autoinflammation and dysmorphic facies; Hyper-IgE recurrent infection syndrome 4B, autosomal recessiveAD/AR

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Dermatologic; Hematologic; Musculoskeletal; Neurologic; Musculoskeletal; Renal

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals have been described as being at increased risk of bacterial infections, and prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 28747427; 30309848; 31914175; 32207811; 33517393

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IL6ST variants in ClinVar

11 Conditions Cataloged

not providedTotal: 557

not specifiedTotal: 162

IL6ST-related disorderTotal: 45

Hyper-IgE recurrent infection syndrome 4A, autosomal dominantTotal: 11

Hyper-IgE recurrent infection syndrome 4, autosomal recessiveTotal: 9

Stuve-Wiedemann syndrome 2Total: 7

Immunodeficiency 94 with autoinflammation and dysmorphic faciesTotal: 5

Developmental and epileptic encephalopathy, 7Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002184.4. 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			6 clinvar	135 clinvar	3 clinvar	144
missense	2 clinvar		357 clinvar	14 clinvar	3 clinvar	376
nonsense	5 clinvar	1 clinvar	1 clinvar			7
start loss						0
frameshift	7 clinvar	2 clinvar	4 clinvar			13
splice donor/acceptor (+/-2bp)		4 clinvar	6 clinvar			10
Total	14	7	374	149	6	550

Highest pathogenic variant AF is 0.000006577476

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 71 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002184.4	RefSeq	NP_002175.2	15	MANE Select
ENST00000381298.7	Ensembl	ENSP00000370698.2	15	MANE Select
NM_001190981.2	RefSeq	NP_001177910.1	14	Standard
NM_001364275.2	RefSeq	NP_001351204.1	14	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)
Jak-STAT signaling pathway - Homo sapiens (human)
Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
Th17 cell differentiation - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)

Biological Process

positive regulation of acute inflammatory response
positive regulation of adaptive immune response
glycogen metabolic process
positive regulation of cell population proliferation
regulation of Notch signaling pathway

Molecular Function

cytokine receptor activity
ciliary neurotrophic factor receptor activity
interleukin-6 receptor activity
interleukin-11 receptor activity
leukemia inhibitory factor receptor activity

Cellular Component

extracellular region
plasma membrane
interleukin-6 receptor complex
oncostatin-M receptor complex
external side of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000381298
Coding exons: 15
Length: 59899
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125747
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.06	408	473	0.863	0.0000229	6014
Missense (PolyPhen)		72	118.59	0.60712		1479
Synonymous	-0.0901	171	170	1.01	0.00000851	1717
Loss of Function	5.61	5	46.2	0.108	0.00000233	573

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	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000082	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Signal-transducing molecule. The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize IL6ST for initiating signal transmission. Binding of IL6 to IL6R induces IL6ST homodimerization and formation of a high-affinity receptor complex, which activates Janus kinases (PubMed:2261637). That causes phosphorylation of IL6ST tyrosine residues which in turn activates STAT3 (PubMed:19915009, PubMed:23294003). Mediates signals which regulate immune response, hematopoiesis, pain control and bone metabolism (By similarity). Has a role in embryonic development (By similarity). Does not bind IL6 (PubMed:2261637). Essential for survival of motor and sensory neurons and for differentiation of astrocytes (By similarity). Required for expression of TRPA1 in nociceptive neurons (By similarity). Required for the maintenance of PTH1R expression in the osteoblast lineage and for the stimulation of PTH-induced osteoblast differentiation (By similarity). Required for normal trabecular bone mass and cortical bone composition (By similarity). {ECO:0000250|UniProtKB:Q00560, ECO:0000269|PubMed:19915009, ECO:0000269|PubMed:2261637, ECO:0000269|PubMed:23294003}.;

Recessive Scores

pRec: 0.764

Intolerance Scores

LoFtool: 0.442
RVIS EVS: 0.54
RVIS percentile EVS: 81.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.965

Gene Damage Prediction

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