IL11RA

protein-coding

interleukin 11 receptor subunit alpha, the group of Interleukin receptors|Immunoglobulin like domain containing

Gene summary

Interleukin 11 is a stromal cell-derived cytokine that belongs to a family of pleiotropic and redundant cytokines that use the gp130 transducing subunit in their high affinity receptors. This gene encodes the IL-11 receptor, which is a member of the hematopoietic cytokine receptor family. This particular receptor is very similar to ciliary neurotrophic factor, since both contain an extracellular region with a 2-domain structure composed of an immunoglobulin-like domain and a cytokine receptor-like domain. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2012]

MANE transcript

NM_001142784.3

Inheritance

ClinVar variants

P:26U:33B:31

Top phenotype

Craniosynostosis and dental anomalies

gnomAD constraint

pLI —, LoF o/e 1.13

Max pathogenic AF

—

Genomic locus

chr9:34,652,162-34,661,902

External References & Databases

Ensembl (ENSG00000137070)

Transcript & Mutation Effects

hg38 • Region Span ~9.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

craniosynostosis and dental anomaliesDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013615

Submitter: ClinGen

*IL11RA* was first reported in relation to autosomal recessive craniosynostosis and dental anomalies (CRSDA) in 2011 by Nieminen et al. (PMID: 21741611). Fifteen variants (missense, duplications, nonsense) that have been reported in over 15 probands in two publications (PMIDs: 21741611, 24498618) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by experimental evidence (mice models, cell cultures, and expression level evidence; PMID: 21741611). Mice models and cell cultures with mutated/homozygous null Il11ra exhibit the phenotype of craniosynostosis with dental anomalies, and the gene has been shown to be expressed in areas of interest in mice. In summary, *IL11RA* is definitively associated with autosomal recessive craniosynostosis with dental anomalies (CRSDA). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniomalformations GCEP on the meeting date 4/20/2023 (SOP Version 9).

craniosynostosis and dental anomaliesDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013615

Submitter: G2P

craniosynostosis and dental anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013615

Submitter: PanelApp Australia

craniosynostosis and dental anomaliesSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013615

Submitter: Orphanet

craniosynostosis and dental anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013615

Submitter: Labcorp Genetics (formerly Invitae)

craniosynostosis and dental anomaliesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013615

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Craniosynostosis and dental anomaliesAR

Manifestation: Craniofacial; Dental

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: 21741611

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IL11RA variants in ClinVar

6 Conditions Cataloged

not providedTotal: 84

Craniosynostosis and dental anomaliesTotal: 15

IL11RA-related disorderTotal: 9

not specifiedTotal: 6

Craniosynostosis syndromeTotal: 2

IL11RA-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001142784.3. 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		1 clinvar	1 clinvar	20 clinvar	2 clinvar	24
missense	3 clinvar	5 clinvar	25 clinvar	6 clinvar	3 clinvar	42
nonsense	5 clinvar	2 clinvar				7
start loss		1 clinvar				1
frameshift	1 clinvar	3 clinvar				4
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	7 clinvar			12
Total	11	15	33	26	5	90

Highest pathogenic variant AF is 0.00009788834

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 101 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001142784.3	RefSeq	NP_001136256.1	12	MANE Select
ENST00000441545.7	Ensembl	ENSP00000394391.3	12	MANE Select
ENST00000318041.13	Ensembl	ENSP00000326500.8	12	Standard
ENST00000318041.14	Ensembl	ENSP00000326500.8	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Jak-STAT signaling pathway - Homo sapiens (human)
Hematopoietic cell lineage - Homo sapiens (human)
Cytokine-cytokine receptor interaction - Homo sapiens (human)
JAK-STAT-Core
Interleukin-11 Signaling Pathway

Biological Process

positive regulation of cell population proliferation
cytokine-mediated signaling pathway
developmental process
interleukin-11-mediated signaling pathway
head development

Molecular Function

transmembrane signaling receptor activity
cytokine receptor activity
interleukin-11 receptor activity
cytokine binding
interleukin-11 binding

Cellular Component

plasma membrane
integral component of plasma membrane
external side of plasma membrane
receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000555003
Coding exons: 12
Length: 11191
Individuals with no LoFs: 125629
Homozygous LoFs: 0
Heterozygous LoFs: 119
Defined: 125748
p: 0.000473

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.637	209	237	0.883	0.0000147	2654
Missense (PolyPhen)		61	67.851	0.89903		828
Synonymous	0.121	95	96.5	0.984	0.00000539	933
Loss of Function	-0.607	29	25.7	1.13	0.00000141	253

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00094	0.00092	rare
Latino/Admixed American	0.00061	0.00061	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00038	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00042	0.00042	rare
South Asian	0.00065	0.00065	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for interleukin-11. The receptor systems for IL6, LIF, OSM, CNTF, IL11 and CT1 can utilize IL6ST for initiating signal transmission. The IL11/IL11RA/IL6ST complex may be involved in the control of proliferation and/or differentiation of skeletogenic progenitor or other mesenchymal cells. Essential for the normal development of craniofacial bones and teeth. Restricts suture fusion and tooth number. {ECO:0000269|PubMed:21741611}.;

Recessive Scores

pRec: 0.0877

Intolerance Scores

LoFtool: 0.942
RVIS EVS: 0
RVIS percentile EVS: 53.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.00121

Gene Damage Prediction

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