IL6ST

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

Basic information

Region (hg38): 5:55935094-55995022

Links

ENSG00000134352 ∙ NCBI:3572 ∙ OMIM:600694 ∙ HGNC:6021 ∙ Uniprot:P40189 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hyper-IgE recurrent infection syndrome 4, autosomal recessive (Strong), mode of inheritance: AR
• hyper-IgE recurrent infection syndrome 4A, autosomal dominant (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hyper-IgE recurrent infection syndrome 4A, autosomal dominant; Immunodeficiency 94 with autoinflammation and dysmorphic facies; Hyper-IgE recurrent infection syndrome 4B, autosomal recessive	AD/AR	Allergy/Immunology/Infectious	Individuals have been described as being at increased risk of bacterial infections, and prophylaxis and early and aggressive treatment of infections may be beneficial	Allergy/Immunology/Infectious; Craniofacial; Dermatologic; Hematologic; Musculoskeletal; Neurologic; Musculoskeletal; Renal	28747427; 30309848; 31914175; 32207811; 33517393

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IL6ST gene.

• not provided (7 variants)
• Stuve-Wiedemann syndrome 2 (1 variants)
• Stuve-Wiedemann syndrome (1 variants)
• Hyper-IgE recurrent infection syndrome 4A, autosomal dominant (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IL6ST gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	79	5	87
missense			247	9	9	265
nonsense	2		1			3
start loss						0
frameshift	5		4			9
inframe indel			1			1
splice donor/acceptor (+/-2bp)		2				2
splice region			10	23	3	36
non coding				32	4	36
Total	7	2	256	120	18

Variants in IL6ST

This is a list of pathogenic ClinVar variants found in the IL6ST region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-55941084-A-T			Uncertain significance (Jul 12, 2023)
5-55941099-C-T			Uncertain significance (May 22, 2022)
5-55941100-G-A			Likely benign (Oct 01, 2023)
5-55941102-C-T			Uncertain significance (Aug 04, 2023)
5-55941103-T-C			Benign (Jan 29, 2024)
5-55941107-C-T			Uncertain significance (Dec 11, 2023)
5-55941108-G-A			Uncertain significance (Aug 11, 2023)
5-55941131-T-A			Uncertain significance (Nov 23, 2022)
5-55941137-A-C			Uncertain significance (Jul 18, 2023)
5-55941137-A-G			Uncertain significance (Dec 10, 2023)
5-55941140-C-T			Uncertain significance (May 15, 2022)
5-55941176-A-T			Uncertain significance (May 01, 2022)
5-55941186-C-T		IL6ST-related disorder	Benign (Jan 19, 2024)
5-55941195-C-G			Uncertain significance (Oct 18, 2023)
5-55941198-T-C			Uncertain significance (Nov 17, 2023)
5-55941200-C-T			Uncertain significance (Dec 04, 2022)
5-55941207-C-G			Uncertain significance (Apr 07, 2022)
5-55941221-G-A		not specified	Uncertain significance (May 26, 2024)
5-55941241-T-A			Uncertain significance (Feb 11, 2023)
5-55941246-T-C			Uncertain significance (Oct 08, 2020)
5-55941257-C-A			Uncertain significance (Sep 24, 2022)
5-55941265-T-C			Likely benign (Aug 02, 2023)
5-55941272-A-G			Uncertain significance (Sep 17, 2023)
5-55941275-T-G			Uncertain significance (Aug 28, 2023)
5-55941276-G-T		not specified	Uncertain significance (May 20, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IL6ST	protein_coding	protein_coding	ENST00000381298	15	59899

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000217	125737	0	10	125747	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.06	408	473	0.863	0.0000229	6014
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000816	0.0000703
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

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}.
• Pathway: 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);Viral carcinogenesis - Homo sapiens (human);Cytokine-cytokine receptor interaction - Homo sapiens (human);JAK-STAT-Core;Physiological and Pathological Hypertrophy of the Heart;MicroRNAs in cardiomyocyte hypertrophy;Interleukin-11 Signaling Pathway;Adipogenesis;Oncostatin M Signaling Pathway;Mammary gland development pathway - Involution (Stage 4 of 4);IL-6 signaling pathway;ESC Pluripotency Pathways;Senescence and Autophagy in Cancer;Interleukin-12 family signaling;Signal Transduction;Signaling by Interleukins;IL-6-type cytokine receptor ligand interactions;Cytokine Signaling in Immune system;JAK STAT MolecularVariation 1;Oncostatin_M;Immune System;AndrogenReceptor;MAPK1 (ERK2) activation;IL-6 signaling;RAF-independent MAPK1/3 activation;SHP2 signaling;JAK STAT MolecularVariation 2;MAPK1/MAPK3 signaling;MAPK family signaling cascades;JAK STAT pathway and regulation;LIF signaling;IL11;Interleukin-27 signaling;IL6;MAPK3 (ERK1) activation;IL27-mediated signaling events;Interleukin-6 signaling;Interleukin-6 family signaling;IL6-mediated signaling events (Consensus)

Recessive Scores

• pRec: 0.764

Intolerance Scores

• loftool: 0.442
• rvis_EVS: 0.54
• rvis_percentile_EVS: 81.07

Haploinsufficiency Scores

• pHI: 0.679
• hipred: Y
• hipred_score: 0.752
• ghis: 0.557

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.965

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Il6st
• Phenotype: digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; vision/eye phenotype; immune system phenotype; skeleton phenotype; embryo phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); normal phenotype; endocrine/exocrine gland phenotype; neoplasm; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype

Gene ontology

• 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;positive regulation of vascular endothelial growth factor production;positive regulation of cardiac muscle hypertrophy;viral process;cytokine-mediated signaling pathway;response to cytokine;interleukin-11-mediated signaling pathway;oncostatin-M-mediated signaling pathway;positive regulation of T cell proliferation;positive regulation of tyrosine phosphorylation of STAT protein;negative regulation of apoptotic process;positive regulation of osteoblast differentiation;positive regulation of astrocyte differentiation;leukemia inhibitory factor signaling pathway;interleukin-6-mediated signaling pathway;interleukin-27-mediated signaling pathway;ciliary neurotrophic factor-mediated signaling pathway;interleukin-35-mediated signaling pathway
• Cellular component: extracellular region;plasma membrane;interleukin-6 receptor complex;oncostatin-M receptor complex;external side of plasma membrane;membrane;dendrite;neuronal cell body;receptor complex;extracellular exosome;ciliary neurotrophic factor receptor complex
• Molecular function: cytokine receptor activity;ciliary neurotrophic factor receptor activity;interleukin-6 receptor activity;interleukin-11 receptor activity;leukemia inhibitory factor receptor activity;oncostatin-M receptor activity;ciliary neurotrophic factor receptor binding;interleukin-6 receptor binding;protein binding;growth factor binding;cytokine binding;interleukin-11 binding;interleukin-6 binding;identical protein binding;protein homodimerization activity;interleukin-27 receptor activity