NBN

nibrin, the group of MRN complex|BRCA1 C complex

Basic information

Region (hg38): 8:89924514-90003228

Previous symbols: [ "NBS", "NBS1" ]

Links

ENSG00000104320 ∙ NCBI:4683 ∙ OMIM:602667 ∙ HGNC:7652 ∙ Uniprot:O60934 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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: CGD

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 ClinVar and linked to the NBN gene.

• Microcephaly, normal intelligence and immunodeficiency (2589 variants)
• Hereditary cancer-predisposing syndrome (1696 variants)
• not provided (612 variants)
• not specified (315 variants)
• Aplastic anemia (252 variants)
• Hereditary breast ovarian cancer syndrome (52 variants)
• Malignant tumor of breast (45 variants)
• Microcephaly, normal intelligence and immunodeficiency;Aplastic anemia;Acute lymphoid leukemia (30 variants)
• Acute lymphoid leukemia (28 variants)
• Inborn genetic diseases (19 variants)
• NBN-related condition (17 variants)
• Acute lymphoid leukemia;Microcephaly, normal intelligence and immunodeficiency;Aplastic anemia (14 variants)
• Gastric cancer (9 variants)
• Microcephaly, normal intelligence and immunodeficiency;Acute lymphoid leukemia;Aplastic anemia (7 variants)
• Aplastic anemia;Acute lymphoid leukemia;Microcephaly, normal intelligence and immunodeficiency (6 variants)
• Aplastic anemia;Microcephaly, normal intelligence and immunodeficiency;Acute lymphoid leukemia (6 variants)
• Hereditary cancer (5 variants)
• Breast and/or ovarian cancer (5 variants)
• Ovarian cancer (4 variants)
• Breast carcinoma (4 variants)
• Familial cancer of breast (3 variants)
• Breast-ovarian cancer, familial, susceptibility to, 1 (3 variants)
• Malignant tumor of prostate (3 variants)
• Ovarian carcinoma (2 variants)
• Diffuse midline glioma, H3 K27-altered (2 variants)
• Malignant lymphoma, large B-cell, diffuse (1 variants)
• Carcinoma of pancreas (1 variants)
• Leukemia, acute lymphoblastic, susceptibility to (1 variants)
• Familial cancer of breast;Lymphoma;Prostate cancer susceptibility (1 variants)
• Hepatocellular carcinoma (1 variants)
• Familial ovarian cancer (1 variants)
• See cases (1 variants)
• Breast cancer, susceptibility to;Microcephaly, normal intelligence and immunodeficiency (1 variants)
• Malignant tumor of breast;Microcephaly, normal intelligence and immunodeficiency (1 variants)
• Microcephaly;Lissencephaly (1 variants)
• Carcinoma of colon (1 variants)
• Microcephaly, normal intelligence and immunodeficiency;Familial cancer of breast (1 variants)
• Premature ovarian insufficiency (1 variants)
• Acute lymphoid leukemia;Aplastic anemia;Microcephaly, normal intelligence and immunodeficiency (1 variants)
• BAP1-related tumor predisposition syndrome (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			8	512	4	524
missense		2	1416	20	1	1439
nonsense	70	50	1			121
start loss			1			1
frameshift	135	114	13			262
inframe indel			36			36
splice donor/acceptor (+/-2bp)	2	88	7	1		98
splice region			85	79	4	168
non coding			59	274	73	406
Total	207	254	1541	807	78

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)
8-89924954-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)
8-89933370-C-T		Microcephaly, normal intelligence and immunodeficiency	Benign (Jan 12, 2018)

GnomAD

Source: gnomAD

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: dbNSFP

• 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