LIG4

DNA ligase 4, the group of DNA ligases

Basic information

Region (hg38): 13:108207439-108218368

Links

ENSG00000174405 ∙ NCBI:3981 ∙ OMIM:601837 ∙ HGNC:6601 ∙ Uniprot:P49917 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• DNA ligase IV deficiency (Definitive), mode of inheritance: AR
• Dubowitz syndrome (Supportive), mode of inheritance: AR
• Omenn syndrome (Supportive), mode of inheritance: AR
• DNA ligase IV deficiency (Supportive), mode of inheritance: AR
• DNA ligase IV deficiency (Strong), mode of inheritance: AR
• DNA ligase IV deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
LIG4 syndrome; Severe combined immunodeficiency with sensitivity to ionizing radiation	AR	Allergy/Immunology/Infectious; Hematologic; Oncologic	Antiinfectious prophylaxis and early and aggressive treatment of infections and hematologic anomalies may be beneficial; Oncologic disorders have also been described, and surveillance may allow prompt treatment	Allergy/Immunology/Infectious; Craniofacial; Hematologic; Musculoskeletal; Neurologic; Oncologic	11779494; 15333585; 16088910; 16357942

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LIG4 gene.

• DNA ligase IV deficiency (67 variants)
• not provided (10 variants)
• LIG4-related disorder (2 variants)
• Inborn genetic diseases (2 variants)
• prenatal LIG4 syndrome with aqueductal stenosis (1 variants)
• Severe combined immunodeficiency disease (1 variants)
• DNA ligase IV deficiency;Multiple myeloma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LIG4 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			1	214	4	219
missense	5	11	290	9	4	319
nonsense	16	3				19
start loss						0
frameshift	48	6				54
inframe indel			4			4
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			20	12	14	46
Total	69	20	315	235	22

Highest pathogenic variant AF is 0.000342

Variants in LIG4

This is a list of pathogenic ClinVar variants found in the LIG4 region.

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

Position	Type	Phenotype	Significance	ClinVar
13-108207452-G-A		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Benign (Jan 12, 2018)
13-108207498-C-T		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Benign (Jan 12, 2018)
13-108207550-C-T		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Benign (Jan 12, 2018)
13-108207627-A-T		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Uncertain significance (Jan 13, 2018)
13-108207676-A-G		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Uncertain significance (Jan 12, 2018)
13-108207677-T-TAAAA		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Likely benign (Jun 14, 2016)
13-108207707-T-A		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Benign (Jan 13, 2018)
13-108207752-T-C		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Uncertain significance (Jan 13, 2018)
13-108207795-C-T		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Uncertain significance (Jan 13, 2018)
13-108207797-G-C		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Uncertain significance (Jan 13, 2018)
13-108207848-A-G		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Benign (Jan 13, 2018)
13-108207856-T-C		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Benign (Jan 12, 2018)
13-108207903-CCAATT-C		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Uncertain significance (Jun 14, 2016)
13-108207919-T-G		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Likely benign (Jan 13, 2018)
13-108207930-TTAAG-T		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Likely benign (Jun 14, 2016)
13-108207970-C-CATT		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Likely benign (Jun 14, 2016)
13-108208008-A-C		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Uncertain significance (Jan 13, 2018)
13-108208047-T-C		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Uncertain significance (Jan 12, 2018)
13-108208181-T-G		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Uncertain significance (Jan 13, 2018)
13-108208227-T-C		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Uncertain significance (Jan 13, 2018)
13-108208242-T-C		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Uncertain significance (Jan 13, 2018)
13-108208248-T-C		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Uncertain significance (Jan 12, 2018)
13-108208291-T-C		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Uncertain significance (Jan 13, 2018)
13-108208329-T-C		DNA ligase IV deficiency • Severe combined immunodeficiency due to DCLRE1C deficiency	Benign (Jul 07, 2018)
13-108208367-C-G		Severe combined immunodeficiency due to DCLRE1C deficiency • DNA ligase IV deficiency	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LIG4	protein_coding	protein_coding	ENST00000356922	1	10930

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000416	0.991	125579	0	168	125747	0.000668

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.202	461	473	0.974	0.0000243	6070
Missense in Polyphen		89	117.94	0.75464		1487
Synonymous	-0.313	164	159	1.03	0.00000797	1695
Loss of Function	2.33	13	25.8	0.504	0.00000144	382

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00208	0.00208
Ashkenazi Jewish	0.000199	0.000198
East Asian	0.000326	0.000326
Finnish	0.0000466	0.0000462
European (Non-Finnish)	0.000792	0.000791
Middle Eastern	0.000326	0.000326
South Asian	0.000588	0.000588
Other	0.000817	0.000815

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Efficiently joins single-strand breaks in a double- stranded polydeoxynucleotide in an ATP-dependent reaction. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. The LIG4-XRCC4 complex is responsible for the NHEJ ligation step, and XRCC4 enhances the joining activity of LIG4. Binding of the LIG4-XRCC4 complex to DNA ends is dependent on the assembly of the DNA- dependent protein kinase complex DNA-PK to these DNA ends. {ECO:0000269|PubMed:10854421, ECO:0000269|PubMed:9809069}.
• Disease: DISEASE: Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-negative/NK-cell-positive with sensitivity to ionizing radiation (RSSCID) [MIM:602450]: A form of severe combined immunodeficiency, a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T- cell-mediated cellular immunity due to a defect in T-cell development. Individuals affected by RS-SCID show defects in the DNA repair machinery necessary for coding joint formation and the completion of V(D)J recombination. A subset of cells from such patients show increased radiosensitivity. {ECO:0000269|PubMed:16357942}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Non-homologous end-joining - Homo sapiens (human);DNA Repair;Disease;Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair;HIV Life Cycle;HIV Infection;2-LTR circle formation;Infectious disease;DNA-PK pathway in nonhomologous end joining;Integration of provirus;Early Phase of HIV Life Cycle (Consensus)

Recessive Scores

• pRec: 0.100

Intolerance Scores

• loftool: 0.531
• rvis_EVS: -0.39
• rvis_percentile_EVS: 27.05

Haploinsufficiency Scores

• pHI: 0.404
• hipred: Y
• hipred_score: 0.608
• ghis: 0.573

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.700

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Lig4
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; digestive/alimentary 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); hematopoietic system phenotype; 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); neoplasm

Zebrafish Information Network

• Gene name: lig4
• Affected structure: double-strand break repair via alternative nonhomologous end joining
• Phenotype tag: abnormal
• Phenotype quality: increased process quality

Gene ontology

• Biological process: single strand break repair;in utero embryonic development;pro-B cell differentiation;DNA replication;DNA ligation;nucleotide-excision repair, DNA gap filling;double-strand break repair;double-strand break repair via nonhomologous end joining;cell cycle;central nervous system development;cell population proliferation;response to X-ray;response to gamma radiation;T cell differentiation in thymus;V(D)J recombination;immunoglobulin V(D)J recombination;T cell receptor V(D)J recombination;somatic stem cell population maintenance;negative regulation of neuron apoptotic process;isotype switching;positive regulation of fibroblast proliferation;positive regulation of neurogenesis;DNA ligation involved in DNA recombination;DNA ligation involved in DNA repair;chromosome organization;cell division;neuron apoptotic process;cellular response to lithium ion;cellular response to ionizing radiation;DNA biosynthetic process;establishment of integrated proviral latency;double-strand break repair via classical nonhomologous end joining;positive regulation of chromosome organization
• Cellular component: nuclear chromosome, telomeric region;condensed chromosome;nucleus;nucleoplasm;DNA-dependent protein kinase-DNA ligase 4 complex;DNA ligase IV complex;cytoplasmic ribonucleoprotein granule;nonhomologous end joining complex
• Molecular function: DNA binding;DNA ligase activity;DNA ligase (ATP) activity;protein binding;ATP binding;protein C-terminus binding;ligase activity;metal ion binding