GeneBe

RNF168

protein-coding

ring finger protein 168, the group of Ring finger proteins

Gene summary

This gene encodes an E3 ubiquitin ligase protein that 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 protein is involved in DNA double-strand break (DSB) repair. Mutations in this gene result in Riddle syndrome. [provided by RefSeq, Sep 2011]

MANE transcript

NM_152617.4

Inheritance

AR

ClinVar variants

P:36U:180B:133

Top phenotype

RIDDLE syndrome

gnomAD constraint

pLI —, LoF o/e 0.84

Max pathogenic AF

—

Genomic locus

chr3:196,468,783-196,503,768

External References & Databases

Ensembl (ENSG00000163961)NCBI Gene (165918)OMIM (612688)HGNC:26661GenCCUniProt (Q8IYW5)AlphaFoldClinVar (RNF168)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~35.0 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

RIDDLE syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012764

Submitter: Ambry Genetics

RIDDLE syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012764

Submitter: G2P

RIDDLE syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012764

Submitter: Labcorp Genetics (formerly Invitae)

RIDDLE syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012764

Submitter: ClinGen

RNF168 was first reported in relation to autosomal recessive RIDDLE syndrome in 2009 (Stewart et al., PMID: 19203578). RIDDLE syndrome is named for its clinical features which include Radiosensitivity, ImmunoDeficiency, Dysmorphic features, and LEarning difficulties. Four variants (nonsense and frameshift) that have been reported in 3 probands in 3 publications are included in this curation (PMIDs: 19203578, 21394101, 29255463). Information regarding the phenotype of heterozygous carriers is limited; however, one parent of a proband was noted to have B cell chronic lymphocytic leukemia (PMID: 19203578). The mechanism of pathogenicity is loss of function. This gene-disease association is supported by biochemical studies, functional and rescue assays, and an animal model (PMIDs: 19203578, 17940005, 29255463, 21394101, 21552324). RNF168 is critical for double stranded break repair (PMID: 19203578), and RIDDLE syndrome patient cells show defects in 53BP1-mediated DNA damage signaling (PMID: 17940005, 29255463). These defects are rescued by wild type RNF168 (PMID: 19203578, 21394101). RNF168 knockout mice have radiosensitivity and immunodeficiency consistent with RIDDLE syndrome (PMID: 21552324). In summary, RNF168 is definitively associated with autosomal recessive RIDDLE syndrome. 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 SCID/CID GCEP on the meeting date July 21, 2022 (SOP Version 9).

RIDDLE syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012764

Submitter: Orphanet

RIDDLE syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012764

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

RIDDLE syndromeAR

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Musculoskeletal; Neurologic; Oncologic

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: Individuals have been described with immunodefiency, as well as radiosensitivity, and thus preventive measures and prophylaxis and early and aggressive treatment of infections may be warranted

Comments: It has been suggested that heterozygotes may demonstrate an increased risk of oncologic processes as well

Refs: 17940005; 19203578; 21394101Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RNF168 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 331
Inborn genetic diseasesTotal: 93
not specifiedTotal: 34
RIDDLE syndromeTotal: 30
RNF168-related disorderTotal: 16
See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152617.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
103
clinvar
1
clinvar
 105
missense
168
clinvar
23
clinvar
6
clinvar
 197
nonsense
2
clinvar
6
clinvar
3
clinvar
 11
start loss
0
frameshift
20
clinvar
5
clinvar
7
clinvar
 32
splice donor/acceptor (+/-2bp)
3
clinvar
1
clinvar
 4
Total22141801267349

Highest pathogenic variant AF is 0.00026809218

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_152617.4RefSeqNP_689830.26MANE Select
ENST00000318037.3EnsemblENSP00000320898.36MANE Select
ENST00000437070.1EnsemblENSP00000396712.12Standard
ENST00001007312.1EnsemblENSP00000677129.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • ATM Signaling Network in Development and Disease
  • HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
  • DNA Repair
  • Nonhomologous End-Joining (NHEJ)
  • DNA Double-Strand Break Repair

Biological Process

  • double-strand break repair
  • double-strand break repair via nonhomologous end joining
  • ubiquitin-dependent protein catabolic process
  • cellular response to DNA damage stimulus
  • response to ionizing radiation

Molecular Function

  • chromatin binding
  • ubiquitin-protein transferase activity
  • protein binding
  • nucleosome binding
  • histone binding

Cellular Component

  • ubiquitin ligase complex
  • nucleus
  • nucleoplasm
  • cytosol
  • protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000318037
Coding exons
6
Length
34986
Individuals with no LoFs
125629
Homozygous LoFs
0
Heterozygous LoFs
118
Defined
125747
p
0.000469
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.3923193001.060.00001543760
Missense (PolyPhen)4851.0450.94034661
Synonymous-0.5051251181.060.000006631068
Loss of Function0.7632226.20.8390.00000137325

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000490.00049rare
Latino/Admixed American0.000750.00075rare
Ashkenazi Jewish0.000700.00069rare
East Asian0.000490.00049rare
Finnish0.0000930.000092rare
European (Non-Finnish)0.000440.00044rare
South Asian0.000520.00052rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8- dependent H2A ubiquitination, promoting the formation of 'Lys-63'- linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively). {ECO:0000255|HAMAP- Rule:MF_03066, ECO:0000269|PubMed:19203578, ECO:0000269|PubMed:19203579, ECO:0000269|PubMed:20550933, ECO:0000269|PubMed:22373579, ECO:0000269|PubMed:22705371, ECO:0000269|PubMed:22713238, ECO:0000269|PubMed:22742833, ECO:0000269|PubMed:22980979, ECO:0000269|PubMed:23760478}.;
Disease
DISEASE: Riddle syndrome (RIDDLES) [MIM:611943]: Characterized by increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature. Defects are probably due to impaired localization of TP53BP1 and BRCA1 at DNA lesions. {ECO:0000269|PubMed:19203578}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0905

Intolerance Scores

LoFtool
0.776
RVIS EVS
0.42
RVIS percentile EVS
77.26

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.938

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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