RNF31

protein-coding

ring finger protein 31, the group of Linear ubiquitin chain assembly complex |RBR E3 ubiquitin ligases|Ring finger proteins|Zinc fingers RANBP2-type

Gene summary

The protein encoded by this gene contains a RING finger, a motif present in a variety of functionally distinct proteins and known to be involved in protein-DNA and protein-protein interactions. The encoded protein is the E3 ubiquitin-protein ligase component of the linear ubiquitin chain assembly complex. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

MANE transcript

NM_017999.5

Inheritance

ClinVar variants

P:3U:466B:266

Top phenotype

Immunodeficiency 115 with autoinflammation

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr14:24,146,683-24,160,660

External References & Databases

Ensembl (ENSG00000092098)

Transcript & Mutation Effects

hg38 • Region Span ~14.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017992

Submitter: Orphanet

immunodeficiency 115 with autoinflammationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0957981

Submitter: ClinGen

*RNF31* (also known as HOIP) was first reported in relation to autosomal recessive immunodeficiency 115 with autoinflammation in 2015 (Boisson et al., PMID 2600889). This condition is also referred to as HOIP deficiency in the literature. HOIP deficiency is characterized by combined immunodeficiency (impaired B cell and T cell lymphocyte function), recurrent bacterial, fungal, and viral infections, abnormal immunoglobulin levels, splenomegaly, systemic inflammation, particularly of the joints, systemic lymphangiectasia, antibody deficiency particularly after vaccination, impaired bone development, and a single case of necrotizing lymphadenitis. At least 4 unique variants (2 missense, 1 frameshift, and 1 intronic) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 3 unrelated probands in 2 publications (PMID 2600889, 30936877, 39009172). There was no evidence of phenotype in heterozygous carriers. The mechanism of pathogenicity appears to be loss of function (LOF). This gene-disease relationship is supported by expression studies, animal models, in vitro functional assays, protein interactions, and rescue in patient derived cells (PMID 26008899, 30936877, 32543267, 33215740, 38582895). RNF31 was demonstrated to interact with SHARPIN and RBCK1, to form the LUBAC complex which is responsible for regulation of the NF-κB pathway through linear ubiquitin chain formation. Disruption to RNF31 protein function showed impaired autophagy processes, presence of inflammatory markers in patient and animal model cells, instability of the LUBAC complex, and susceptibility to infection. Animal models partially recapitulated the phenotype observed in individuals. In summary, there is moderate evidence to support this gene-disease relationship. This classification was approved by the ClinGen SCID/CID Gene Curation Expert Panel on 7/18/2024 (SOP Version [11]).

immunodeficiency 115 with autoinflammationLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0957981

Submitter: Ambry Genetics

immunodeficiency 115 with autoinflammationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0957981

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Immunodeficiency 115 with autoinflammationAR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: The condition involves susceptibility to infections, and and prophylactic measures, as well as early and aggressive treatment of infections with consideration of vaccine regimen, may be beneficial; For autoimmune sequelae, medical management (eg, with TNF antagonists), has been reported to be beneficial

Refs: 26008899; 30936877

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RNF31 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 838

not specifiedTotal: 206

RNF31-related disorderTotal: 20

Immunodeficiency 115 with autoinflammationTotal: 4

Short statureTotal: 2

Polyglucosan body myopathy type 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017999.5. 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			6 clinvar	242 clinvar	4 clinvar	252
missense	2 clinvar	1 clinvar	439 clinvar	18 clinvar	2 clinvar	462
nonsense			7 clinvar			7
start loss						0
frameshift			8 clinvar			8
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	2	1	466	260	6	735

Highest pathogenic variant AF is 0.0000020521325

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017999.5	RefSeq	NP_060469.4	21	MANE Select
ENST00000324103.11	Ensembl	ENSP00000315112.6	21	MANE Select
NM_001310332.2	RefSeq	NP_001297261.1	19	Standard
ENST00000483895.5	Ensembl	ENSP00000453672.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Necroptosis - Homo sapiens (human)
NOD-like receptor signaling pathway - Homo sapiens (human)
Regulation of toll-like receptor signaling pathway
Signal Transduction
TNFR1-induced NFkappaB signaling pathway

Biological Process

protein polyubiquitination
I-kappaB kinase/NF-kappaB signaling
regulation of tumor necrosis factor-mediated signaling pathway
CD40 signaling pathway
positive regulation of I-kappaB kinase/NF-kappaB signaling

Molecular Function

ubiquitin-protein transferase activity
protein binding
ubiquitin protein ligase binding
ubiquitin binding
metal ion binding

Cellular Component

cytosol
cytoplasmic side of plasma membrane
CD40 receptor complex
LUBAC complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000324103
Coding exons: 21
Length: 13979
Individuals with no LoFs: 124805
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 124818
p: 0.0000521

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.14	493	646	0.764	0.0000389	6883
Missense (PolyPhen)		122	225.01	0.5422		2416
Synonymous	-0.970	273	253	1.08	0.0000137	2235
Loss of Function	6.60	6	62.2	0.0965	0.00000353	618

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000071	0.000071	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase component of the LUBAC complex which conjugates linear ('Met-1'-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation (PubMed:17006537, PubMed:19136968, PubMed:20005846, PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22863777, PubMed:28189684). LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways (PubMed:17006537, PubMed:19136968, PubMed:20005846, PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22863777, PubMed:28189684). Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation (PubMed:21455173, PubMed:28189684). LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex (PubMed:20005846, PubMed:27458237). Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis (PubMed:23708998). Binds polyubiquitin of different linkage types (PubMed:23708998). {ECO:0000269|PubMed:17006537, ECO:0000269|PubMed:19136968, ECO:0000269|PubMed:20005846, ECO:0000269|PubMed:21455173, ECO:0000269|PubMed:21455180, ECO:0000269|PubMed:21455181, ECO:0000269|PubMed:22863777, ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:27458237, ECO:0000269|PubMed:28189684}.;

Recessive Scores

pRec: 0.387

Intolerance Scores

LoFtool: 0.427
RVIS EVS: -0.57
RVIS percentile EVS: 19.01

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.964

Gene Damage Prediction

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