RNF168

ring finger protein 168, the group of Ring finger proteins

Basic information

Region (hg38): 3:196468782-196503768

Links

ENSG00000163961 ∙ NCBI:165918 ∙ OMIM:612688 ∙ HGNC:26661 ∙ Uniprot:Q8IYW5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• RIDDLE syndrome (Limited), mode of inheritance: AR
• RIDDLE syndrome (Moderate), mode of inheritance: AR
• RIDDLE syndrome (Strong), mode of inheritance: AR
• RIDDLE syndrome (Supportive), mode of inheritance: AR
• RIDDLE syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
RIDDLE syndrome	AR	Allergy/Immunology/Infectious; Oncologic	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	Allergy/Immunology/Infectious; Craniofacial; Musculoskeletal; Neurologic; Oncologic	17940005; 19203578; 21394101
It has been suggested that heterozygotes may demonstrate an increased risk of oncologic processes as well

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RNF168 gene.

• not provided (14 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RNF168 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	71	3	76
missense			130	6	8	144
nonsense	3	2	3			8
start loss						0
frameshift	11	1	5			17
inframe indel			2			2
splice donor/acceptor (+/-2bp)		2				2
splice region			2	9		11
non coding			1	24	4	29
Total	14	5	143	101	15

Highest pathogenic variant AF is 0.000729

Variants in RNF168

This is a list of pathogenic ClinVar variants found in the RNF168 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-196471828-G-A			Likely benign (Sep 09, 2023)
3-196471829-C-T			Uncertain significance (Jul 02, 2022)
3-196471834-C-A			Uncertain significance (Oct 18, 2022)
3-196471834-C-T			Likely benign (Dec 13, 2023)
3-196471836-GA-G			Uncertain significance (Feb 07, 2021)
3-196471855-T-C			Likely benign (Jan 11, 2024)
3-196471858-C-G		Inborn genetic diseases	Uncertain significance (Mar 08, 2024)
3-196471867-G-A			Likely benign (Nov 24, 2022)
3-196471869-T-C			Uncertain significance (Feb 10, 2022)
3-196471876-T-C			Likely benign (Mar 14, 2022)
3-196471878-G-T			Uncertain significance (Jan 30, 2023)
3-196471882-G-A			Likely benign (Jun 01, 2018)
3-196471885-A-T			Likely benign (Aug 31, 2023)
3-196471902-T-C			Uncertain significance (Jul 19, 2022)
3-196471929-T-C		RNF168-related disorder	Uncertain significance (Oct 27, 2022)
3-196471939-A-G			Likely benign (Jan 02, 2024)
3-196471940-T-TTAAC		RIDDLE syndrome	Uncertain significance (Feb 01, 2022)
3-196471967-A-C			Uncertain significance (Jul 23, 2022)
3-196471987-G-A			Likely benign (Nov 24, 2023)
3-196471987-G-C			Uncertain significance (Oct 11, 2021)
3-196471996-G-C			Likely benign (Apr 02, 2021)
3-196471997-C-A		Inborn genetic diseases	Uncertain significance (Sep 17, 2021)
3-196471997-CCT-C		Inborn genetic diseases	Uncertain significance (Oct 13, 2022)
3-196472007-G-A		Inborn genetic diseases	Likely benign (Apr 17, 2021)
3-196472015-T-C			Uncertain significance (Aug 21, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RNF168	protein_coding	protein_coding	ENST00000318037	6	34986

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.05e-13	0.115	125629	0	118	125747	0.000469

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.392	319	300	1.06	0.0000154	3760
Missense in Polyphen		48	51.045	0.94034		661
Synonymous	-0.505	125	118	1.06	0.00000663	1068
Loss of Function	0.763	22	26.2	0.839	0.00000137	325

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00124	0.00124
Ashkenazi Jewish	0.000696	0.000695
East Asian	0.000489	0.000489
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.000440	0.000440
Middle Eastern	0.000489	0.000489
South Asian	0.000523	0.000523
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;SUMOylation of DNA damage response and repair proteins;Homology Directed Repair;Post-translational protein modification;SUMO E3 ligases SUMOylate target proteins;Metabolism of proteins;G2/M DNA damage checkpoint;G2/M Checkpoints;Cell Cycle Checkpoints;SUMOylation;Cell Cycle;Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks;DNA Double Strand Break Response;Processing of DNA double-strand break ends (Consensus)

Recessive Scores

• pRec: 0.0905

Intolerance Scores

• loftool: 0.776
• rvis_EVS: 0.42
• rvis_percentile_EVS: 77.26

Haploinsufficiency Scores

• pHI: 0.0833
• hipred: Y
• hipred_score: 0.518
• ghis: 0.513

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.938

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rnf168
• Phenotype: immune system phenotype; neoplasm; hematopoietic system phenotype; reproductive system phenotype; cellular phenotype; endocrine/exocrine gland phenotype

Gene ontology

• 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;protein ubiquitination;negative regulation of transcription elongation from RNA polymerase II promoter;histone H2A monoubiquitination;interstrand cross-link repair;histone H2A-K13 ubiquitination;histone H2A-K15 ubiquitination;isotype switching;positive regulation of DNA repair;protein K63-linked ubiquitination;histone H2A K63-linked ubiquitination
• Cellular component: ubiquitin ligase complex;nucleus;nucleoplasm;cytosol;protein-containing complex;site of double-strand break
• Molecular function: chromatin binding;ubiquitin-protein transferase activity;protein binding;nucleosome binding;histone binding;ubiquitin binding;metal ion binding;K63-linked polyubiquitin modification-dependent protein binding