RNF216

protein-coding

ring finger protein 216, the group of MicroRNA protein coding host genes|Ring finger proteins|RBR E3 ubiquitin ligases

Gene summary

This gene encodes a cytoplasmic protein which specifically colocalizes and interacts with the serine/threonine protein kinase, receptor-interacting protein (RIP). Zinc finger domains of the encoded protein are required for its interaction with RIP and for inhibition of TNF- and IL1-induced NF-kappa B activation pathways. The encoded protein may also function as an E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes and transfers it to substrates. Several alternatively spliced transcript variants have been described for this locus but the full-length natures of only some are known. [provided by RefSeq, Jul 2008]

MANE transcript

NM_207111.4

Inheritance

ClinVar variants

P:27U:238B:128

Top phenotype

Cerebellar ataxia and hypogonadotropic hypogonadism (Gordon Holmes syndrome)

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr7:5,620,047-5,781,696

External References & Databases

Ensembl (ENSG00000011275)

Transcript & Mutation Effects

hg38 • Region Span ~161.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebellar ataxia-hypogonadism syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008935

Submitter: PanelApp Australia

cerebellar ataxia-hypogonadism syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008935

Submitter: Ambry Genetics

cerebellar ataxia-hypogonadism syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008935

Submitter: Labcorp Genetics (formerly Invitae)

cerebellar ataxia-hypogonadism syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008935

Submitter: Orphanet

cerebellar ataxia-hypogonadism syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008935

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Cerebellar ataxia and hypogonadotropic hypogonadism (Gordon Holmes syndrome)AR

Manifestation: Endocrine; Neurologic

Intervention: Endocrine

Rationale: Individuals have been described with response to medical treatment (eg, exogenous GnRH therapy), though with progressive loss of pituitary function such that response to treatment decreased and was lost later in the course of disease

Refs: 11932290; 23656588

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RNF216 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 262

Inborn genetic diseasesTotal: 148

not specifiedTotal: 65

Cerebellar ataxia-hypogonadism syndromeTotal: 30

RNF216-related disorderTotal: 18

Hypogonadotropic hypogonadism 7 with or without anosmiaTotal: 1

LeukodystrophyTotal: 1

Rosette-forming glioneuronal tumorTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_207111.4. 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		1 clinvar	1 clinvar	106 clinvar	5 clinvar	113
missense	2 clinvar	4 clinvar	234 clinvar	17 clinvar		257
nonsense	8 clinvar	1 clinvar				9
start loss			1 clinvar			1
frameshift	4 clinvar	4 clinvar	1 clinvar			9
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	1 clinvar			4
Total	15	12	238	123	5	393

Highest pathogenic variant AF is 0.00016424544

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_207111.4	RefSeq	NP_996994.1	16	MANE Select
ENST00000389902.8	Ensembl	ENSP00000374552.3	16	MANE Select
NM_001377156.1	RefSeq	NP_001364085.1	16	Standard
NM_207116.3	RefSeq	NP_996999.1	16	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
rnf216	Danio rerio	Structure: head Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

rnf216

Danio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Regulation of toll-like receptor signaling pathway
Gastric Cancer Network 1
protein ubiquitylation

Biological Process

apoptotic process
viral process
negative regulation of type I interferon production
regulation of interferon-beta production
proteasome-mediated ubiquitin-dependent protein catabolic process

Molecular Function

protein binding
metal ion binding
ubiquitin protein ligase activity

Cellular Component

nucleus
nucleoplasm
cytosol
Schaffer collateral - CA1 synapse
postsynaptic endocytic zone

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000389902
Coding exons: 16
Length: 161693
Individuals with no LoFs: 125716
Homozygous LoFs: 1
Heterozygous LoFs: 31
Defined: 125748
p: 0.000127

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.23	598	519	1.15	0.0000287	6128
Missense (PolyPhen)		208	224.48	0.9266		2635
Synonymous	-3.25	252	194	1.30	0.0000116	1678
Loss of Function	4.11	19	50.6	0.376	0.00000285	575

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000063	0.000062	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.00016	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 1 acts as an E3 ubiquitin ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Promotes degradation of TRAF3, TLR4 and TLR9. Contributes to the regulation of antiviral responses. Down- regulates activation of NF-kappa-B, IRF3 activation and IFNB production. Isoform 3 inhibits TNF and IL-1 mediated activation of NF-kappa-B. Promotes TNF and RIP mediated apoptosis. {ECO:0000269|PubMed:15107846, ECO:0000269|PubMed:19893624}.;
Disease: DISEASE: Gordon Holmes syndrome (GDHS) [MIM:212840]: A disease characterized by cerebellar symptoms and signs of sex steroid deficiency. Clinical features include cerebellar and brain stem atrophy, cerebellar ataxia, hypothalamic LHRH deficiency, hypogonadotrophic hypogonadism, lack of secondary sexual characteristics, and infertility. {ECO:0000269|PubMed:23656588}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0899

Intolerance Scores

LoFtool: 0.596
RVIS EVS: -1.19
RVIS percentile EVS: 5.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.869

Gene Damage Prediction

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