IL17RD

protein-coding

interleukin 17 receptor D, the group of Interleukin receptors|TIR domain containing

Gene summary

This gene encodes a membrane protein belonging to the interleukin-17 receptor (IL-17R) protein family. The encoded protein is a component of the interleukin-17 receptor signaling complex, and the interaction between this protein and IL-17R does not require the interleukin. The gene product also affects fibroblast growth factor signaling, inhibiting or stimulating growth through MAPK/ERK signaling. Alternate splicing generates multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2016]

MANE transcript

NM_017563.5

Inheritance

AD, SD, Digenic

ClinVar variants

P:5U:184B:68

Top phenotype

Hypogonadotropic hypogonadism 18, with or without anosmia

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr3:57,089,982-57,170,306

External References & Databases

Ensembl (ENSG00000144730)

Transcript & Mutation Effects

hg38 • Region Span ~80.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypogonadotropic hypogonadism 18 with or without anosmiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014103

Submitter: Labcorp Genetics (formerly Invitae)

hypogonadotropic hypogonadism 18 with or without anosmiaLIMITED

Inheritance Pattern: SD

Disease ID:MONDO:0014103

Submitter: PanelApp Australia

Kallmann syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018800

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hypogonadotropic hypogonadism 18, with or without anosmiaAD/Digenic

Manifestation: Audiologic/Otolaryngologic; Dental; Endocrine; Musculoskeletal; Neurologic

Intervention: Audiologic/Otolaryngologic; Endocrine

Rationale: In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required; Congenital hearing loss in individuals is typically (though not always) described as unilateral, and recognition and interventions related to speech and language development may be beneficial

Comments: Relatively complex genetic models of disease have been described (eg, involving variants in other FGF8-network-associated genes)

Refs: 23643382

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IL17RD variants in ClinVar

10 Conditions Cataloged

not providedTotal: 155

not specifiedTotal: 143

IL17RD-related disorderTotal: 27

Hypogonadotropic hypogonadism 18 with or without anosmiaTotal: 12

Hypogonadotropic hypogonadism 18 with anosmiaTotal: 3

Delayed pubertyTotal: 3

HYPOGONADOTROPIC HYPOGONADISM 18 WITH ANOSMIA, SUSCEPTIBILITY TOTotal: 2

Cerebral arteriovenous malformationTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017563.5. 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			3 clinvar	55 clinvar		58
missense	2 clinvar	2 clinvar	171 clinvar	10 clinvar	3 clinvar	188
nonsense		1 clinvar	5 clinvar			6
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	2	3	184	65	3	257

Highest pathogenic variant AF is 0.000040275907

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_017563.5	RefSeq	NP_060033.3	13	MANE Select
ENST00000296318.12	Ensembl	ENSP00000296318.7	13	MANE Select
NM_001318864.2	RefSeq	NP_001305793.1	9	Standard
ENST00000320057.10	Ensembl	ENSP00000322250.5	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
il17rd	Danio rerio	Structure: posterior lateral line primordium Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

il17rd

Danio rerio

Structure: posterior lateral line primordium

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

IL17 signaling pathway
Pathways Affected in Adenoid Cystic Carcinoma
MAP2K and MAPK activation
Signal Transduction
EGFR1

Biological Process

MAPK cascade
cytokine-mediated signaling pathway

Molecular Function

interleukin-17 receptor activity

Cellular Component

Golgi membrane
nucleoplasm
Golgi apparatus
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296318
Coding exons: 13
Length: 80325
Individuals with no LoFs: 125572
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125609
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.278	415	431	0.962	0.0000264	4795
Missense (PolyPhen)		108	112.74	0.95796		1338
Synonymous	0.0166	191	191	0.998	0.0000136	1431
Loss of Function	3.01	16	35.3	0.453	0.00000192	406

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000054	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00020	0.00019	rare
South Asian	0.00017	0.00016	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Feedback inhibitor of fibroblast growth factor mediated Ras-MAPK signaling and ERK activation. May inhibit FGF-induced FGFR1 tyrosine phosphorylation. Regulates the nuclear ERK signaling pathway by spatially blocking nuclear translocation of activated ERK without inhibiting cytoplasmic phosphorylation of ERK. Mediates JNK activation and may be involved in apoptosis. Might have a role in the early stages of fate specification of GnRH-secreting neurons (By similarity). {ECO:0000250, ECO:0000269|PubMed:12807873, ECO:0000269|PubMed:12958313, ECO:0000269|PubMed:15239952}.;

Recessive Scores

pRec: 0.124

Intolerance Scores

LoFtool: 0.690
RVIS EVS: -0.17
RVIS percentile EVS: 40.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.242

Gene Damage Prediction

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