NBN
nibrin, the group of MRN complex|BRCA1 C complex
Basic information
Region (hg38): 8:89924515-90003228
Previous symbols: [ "NBS", "NBS1" ]
Links
Phenotypes
GenCC
Source:
- Nijmegen breakage syndrome (Definitive), mode of inheritance: AR
- Nijmegen breakage syndrome (Definitive), mode of inheritance: AR
- rhabdomyosarcoma (Moderate), mode of inheritance: AR
- Nijmegen breakage syndrome (Supportive), mode of inheritance: AR
- idiopathic aplastic anemia (Limited), mode of inheritance: AD
- Nijmegen breakage syndrome (Strong), mode of inheritance: AR
- prostate cancer (Limited), mode of inheritance: AD
- Nijmegen breakage syndrome (Definitive), mode of inheritance: AR
- hereditary breast carcinoma (Refuted Evidence), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Breast cancer, susceptibility to; Nijmegen breakage syndrome | AD/AR | Allergy/Immunology/Infectious; Hematologic; Oncologic | In Breast cancer, susceptibility to, awareness may allow surveillance, preventive measures, and early recognition and treatment of disease; Nijmegen breakage syndrome may be recognizable, but surveillance for cancer may be beneficial, and specific treatment modalities may be preferable (eg, cytostatics are first-line, radiomimetics and radiation therapy should be avoided, and reduced-dose chemotherapy should be used); Surveillance and prompt treatment of hematologic manifestations (eg, aplastic anemia, bone marrow failure) may be beneficial; Due to immunodeficiency, early and aggressive treatment of infections can be beneficial | Allergy/Immunology/Infectious; Hematologic; Musculoskeletal; Neurologic; Oncologic | 3802554; 7545870; 8929954; 9590181; 9590180; 15474156; 15338273; 16634478; 16033915; 20143155; 21166880; 21799032; 21700777; 20143155; 21656575; 22006311; 22070649; 22114071; 22373003; 22491912; 22864661 |
| Variants may result in increased risk of a number of malignancies, including acute lymphoblastic leukemia |
ClinVar
This is a list of variants' phenotypes submitted to
- Microcephaly, normal intelligence and immunodeficiency (175 variants)
- Hereditary cancer-predisposing syndrome (81 variants)
- Aplastic anemia (11 variants)
- not provided (9 variants)
- Breast and/or ovarian cancer (4 variants)
- Breast carcinoma (3 variants)
- Microcephaly, normal intelligence and immunodeficiency;Acute lymphoid leukemia;Aplastic anemia (2 variants)
- Malignant tumor of breast (2 variants)
- NBN-related disorder (2 variants)
- Carcinoma of pancreas (1 variants)
- Ovarian carcinoma (1 variants)
- Breast-ovarian cancer, familial, susceptibility to, 1 (1 variants)
- Familial cancer of breast;Microcephaly, normal intelligence and immunodeficiency (1 variants)
- Hepatocellular carcinoma (1 variants)
- Premature ovarian insufficiency (1 variants)
- Lissencephaly;Microcephaly (1 variants)
- Gastric cancer (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the NBN 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 | 545 | 556 | ||||
| missense | 1476 | 24 | 1504 | |||
| nonsense | 73 | 55 | 129 | |||
| start loss | 1 | |||||
| frameshift | 137 | 126 | 14 | 277 | ||
| inframe indel | 38 | 38 | ||||
| splice donor/acceptor (+/-2bp) | 89 | 101 | ||||
| splice region | 88 | 91 | 4 | 183 | ||
| non coding | 63 | 309 | 72 | 444 | ||
| Total | 213 | 273 | 1608 | 879 | 77 |
Highest pathogenic variant AF is 0.000197
Variants in NBN
This is a list of pathogenic ClinVar variants found in the NBN region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 8-89924544-G-A | not specified | Uncertain significance (Jan 08, 2024) | ||
| 8-89924615-G-A | not specified | Uncertain significance (Apr 25, 2022) | ||
| 8-89924665-T-A | not specified | Uncertain significance (Nov 10, 2022) | ||
| 8-89924701-C-A | not specified | Likely benign (Jan 26, 2023) | ||
| 8-89924708-A-C | not specified | Uncertain significance (Jan 26, 2023) | ||
| 8-89924709-A-G | not specified | Uncertain significance (Oct 25, 2023) | ||
| 8-89924710-G-C | not specified | Uncertain significance (Aug 23, 2021) | ||
| 8-89924739-G-A | not specified | Uncertain significance (Nov 17, 2023) | ||
| 8-89924836-A-C | not specified | Uncertain significance (Dec 19, 2022) | ||
| 8-89924867-A-G | not specified | Uncertain significance (Aug 13, 2021) | ||
| 8-89924900-A-C | not specified | Uncertain significance (Aug 08, 2023) | ||
| 8-89924906-C-T | not specified | Uncertain significance (Sep 13, 2023) | ||
| 8-89924933-G-T | not specified | Uncertain significance (Jun 07, 2024) | ||
| 8-89924954-G-A | not specified | Uncertain significance (Jan 20, 2023) | ||
| 8-89924970-G-C | Benign (Jul 16, 2018) | |||
| 8-89925128-T-C | Likely benign (Mar 01, 2022) | |||
| 8-89925182-A-G | not specified | Uncertain significance (Jan 30, 2024) | ||
| 8-89925183-T-C | not specified | Uncertain significance (Dec 21, 2021) | ||
| 8-89925224-T-A | not specified | Uncertain significance (Jun 30, 2022) | ||
| 8-89925224-T-C | not specified | Uncertain significance (Feb 07, 2023) | ||
| 8-89925243-T-C | not specified | Uncertain significance (Aug 11, 2022) | ||
| 8-89925284-G-A | not specified | Uncertain significance (Dec 21, 2021) | ||
| 8-89925428-C-G | not specified | Uncertain significance (Sep 21, 2023) | ||
| 8-89925462-G-A | not specified | Uncertain significance (May 09, 2022) | ||
| 8-89933330-A-T | Microcephaly, normal intelligence and immunodeficiency | Uncertain significance (Jan 12, 2018) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| NBN | protein_coding | protein_coding | ENST00000265433 | 16 | 69893 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 2.18e-16 | 0.343 | 125623 | 0 | 125 | 125748 | 0.000497 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 0.609 | 344 | 377 | 0.912 | 0.0000178 | 4974 |
| Missense in Polyphen | 74 | 81.197 | 0.91136 | 1125 | ||
| Synonymous | -0.676 | 145 | 135 | 1.07 | 0.00000707 | 1362 |
| Loss of Function | 1.50 | 30 | 40.3 | 0.745 | 0.00000194 | 518 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000605 | 0.000601 |
| Ashkenazi Jewish | 0.000298 | 0.000298 |
| East Asian | 0.000163 | 0.000163 |
| Finnish | 0.000370 | 0.000370 |
| European (Non-Finnish) | 0.000706 | 0.000703 |
| Middle Eastern | 0.000163 | 0.000163 |
| South Asian | 0.000392 | 0.000392 |
| Other | 0.000822 | 0.000815 |
dbNSFP
Source:
- Function
- FUNCTION: Component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. The complex is involved in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity, cell cycle checkpoint control and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. NBN modulate the DNA damage signal sensing by recruiting PI3/PI4-kinase family members ATM, ATR, and probably DNA-PKcs to the DNA damage sites and activating their functions. It can also recruit MRE11 and RAD50 to the proximity of DSBs by an interaction with the histone H2AX. NBN also functions in telomere length maintenance by generating the 3' overhang which serves as a primer for telomerase dependent telomere elongation. NBN is a major player in the control of intra-S-phase checkpoint and there is some evidence that NBN is involved in G1 and G2 checkpoints. The roles of NBS1/MRN encompass DNA damage sensor, signal transducer, and effector, which enable cells to maintain DNA integrity and genomic stability. Forms a complex with RBBP8 to link DNA double-strand break sensing to resection. Enhances AKT1 phosphorylation possibly by association with the mTORC2 complex. {ECO:0000269|PubMed:10888888, ECO:0000269|PubMed:15616588, ECO:0000269|PubMed:19759395, ECO:0000269|PubMed:23762398, ECO:0000269|PubMed:9705271}.;
- Disease
- DISEASE: Nijmegen breakage syndrome (NBS) [MIM:251260]: A disorder characterized by chromosomal instability, radiation sensitivity, microcephaly, growth retardation, immunodeficiency and predisposition to cancer, particularly to lymphoid malignancies. {ECO:0000269|PubMed:9590180}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:14684699}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Aplastic anemia (AA) [MIM:609135]: A form of anemia in which the bone marrow fails to produce adequate numbers of peripheral blood elements. It is characterized by peripheral pancytopenia and marrow hypoplasia. {ECO:0000269|PubMed:15338273}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Note=Defects in NBN might play a role in the pathogenesis of childhood acute lymphoblastic leukemia (ALL). {ECO:0000269|PubMed:11325820}.;
- Pathway
- Homologous recombination - Homo sapiens (human);Cellular senescence - Homo sapiens (human);miRNA Regulation of DNA Damage Response;Homologous recombination;DDX1 as a regulatory component of the Drosha microprocessor;ATM Signaling Network in Development and Disease;DNA Damage Response;HDR through Single Strand Annealing (SSA);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);HDR through MMEJ (alt-NHEJ);DNA Repair;Gene expression (Transcription);Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair;role of brca1 brca2 and atr in cancer susceptibility;Generic Transcription Pathway;DNA Damage/Telomere Stress Induced Senescence;Cellular Senescence;Homology Directed Repair;Cellular responses to stress;RNA Polymerase II Transcription;G2/M DNA damage checkpoint;G2/M Checkpoints;Cell Cycle Checkpoints;Cellular responses to external stimuli;Fanconi anemia pathway;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Sensing of DNA Double Strand Breaks;Cell Cycle;Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks;DNA Double Strand Break Response;Validated targets of C-MYC transcriptional activation;Regulation of Telomerase;BARD1 signaling events;Processing of DNA double-strand break ends;ATM pathway;ATR signaling pathway;Presynaptic phase of homologous DNA pairing and strand exchange;Homologous DNA Pairing and Strand Exchange;Resolution of D-loop Structures through Holliday Junction Intermediates;Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA);Resolution of D-Loop Structures;HDR through Homologous Recombination (HRR)
(Consensus)
Recessive Scores
- pRec
- 0.653
Intolerance Scores
- loftool
- 0.811
- rvis_EVS
- 1.64
- rvis_percentile_EVS
- 96.17
Haploinsufficiency Scores
- pHI
- 0.844
- hipred
- Y
- hipred_score
- 0.566
- ghis
- 0.432
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- H
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.755
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Nbn
- Phenotype
- immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); neoplasm; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; cellular phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype;
Gene ontology
- Biological process
- DNA damage checkpoint;telomere maintenance;double-strand break repair via homologous recombination;DNA double-strand break processing;blastocyst growth;DNA replication;double-strand break repair;double-strand break repair via nonhomologous end joining;cell cycle arrest;mitotic cell cycle checkpoint;mitotic G2 DNA damage checkpoint;cell population proliferation;telomere capping;regulation of DNA-dependent DNA replication initiation;DNA damage response, signal transduction by p53 class mediator;telomeric 3' overhang formation;positive regulation of protein autophosphorylation;positive regulation of telomere maintenance;DNA duplex unwinding;positive regulation of kinase activity;signal transduction in response to DNA damage;isotype switching;neuromuscular process controlling balance;meiotic cell cycle;t-circle formation;telomere maintenance via telomere trimming;intrinsic apoptotic signaling pathway;negative regulation of telomere capping
- Cellular component
- nuclear chromosome, telomeric region;nucleus;nucleoplasm;replication fork;nucleolus;cytosol;PML body;Mre11 complex;site of double-strand break;nuclear inclusion body
- Molecular function
- damaged DNA binding;ATP-dependent DNA helicase activity;protein binding;transcription factor binding;protein N-terminus binding