LIG4
protein-codingDNA ligase 4, the group of DNA ligases
Gene summary
The protein encoded by this gene is a DNA ligase that joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. This protein is essential for V(D)J recombination and DNA double-strand break (DSB) repair through nonhomologous end joining (NHEJ). This protein forms a complex with the X-ray repair cross complementing protein 4 (XRCC4), and further interacts with the DNA-dependent protein kinase (DNA-PK). Both XRCC4 and DNA-PK are known to be required for NHEJ. The crystal structure of the complex formed by this protein and XRCC4 has been resolved. Defects in this gene are the cause of LIG4 syndrome. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011686
Submitter: ClinGen
LIG4- SCID autosomal recessive Phenotype MIM:600802 LIG4 deficiency was first reported in a patient in 1990 (Plowman et al., PMID: 2400879). A fibroblast line from the patient was further investigated and identified mutated DNA LIG4 in relation to autosomal recessive SCID in 1999(Riballo et al., PMID 10395545). Since this first case was described, 27 further cases have been published with a broad spectrum of clinical features ranging from Microcephaly, developmental delay, lymphopenia, and other features. LIG4 is part of a end joining mechanism required in repairing DNA double stranded breaks. It is universally expressed and required to avert apoptosis and mutagenesis. DNA LIG4 also is involved in repairing programmed DNA double stranded breaks during lymphocyte receptor development. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants have been reported in 12 cases globally with combined immunodeficiency with T- and B- Lymphocytopenia, in at least 7 publications(PMID: 31604460, PMID 11779494, PMID 17224058, PMID 16088910, PMID 27063650, PMID 16358361, PMID 24123394). Probands described range in age of onset between 3 months to 48 years. The clinical manifestation of immunodeficiency may be due to a accumulation of DNA double-strand break which would lead to progressive apoptosis in lymphocyte progenitors of LIG4 patients based on the reduction of lymphocytes over time(PMID: 23722522). A family with three affected siblings showed varying cellular and molecular phenotypes with only one truly affected sibling suggesting the phenotype can dramatically vary(PMID: 27063650). This gene-disease association is supported by mouse models, functional alteration, and expression studies(PMID: 2013615, PMID:24889605, PMID: 109119933, PMID:11779494). Complete knockout of LIG4 in mice is embryological lethal and mutations described in humans are hypomorphic, leading to significantly impaired Non-homologous end joining but still maintaining some activity( PMID: 10911993). In summary, LIG4 is definitively associated with autosomal recessive, severe combined immunodeficiency disease and combined immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time
Inheritance Pattern: AR
Disease ID:MONDO:0011686
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011686
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011686
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011686
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Craniofacial; Hematologic; Musculoskeletal; Neurologic; Oncologic
Intervention: Allergy/Immunology/Infectious; Hematologic; Oncologic
Rationale: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LIG4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_206937.2. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 265 | 3 | 268 | |||
| missense | 6 | 19 | 352 | 23 | 2 | 402 |
| nonsense | 17 | 8 | 25 | |||
| start loss | 0 | |||||
| frameshift | 57 | 12 | 69 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 80 | 39 | 352 | 288 | 5 | 764 |
Highest pathogenic variant AF is 0.00021953162
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_996820.1 | 1 | MANE Select | |
| Ensembl | ENSP00000402030.1 | 1 | MANE Select | |
| RefSeq | NP_001091738.1 | 1 | Standard | |
| RefSeq | NP_001317524.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| lig4 | Danio rerio | Structure: double-strand break repair via alternative nonhomologous end joining Quality: increased process quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Non-homologous end-joining - Homo sapiens (human)
- DNA Repair
- Disease
- Nonhomologous End-Joining (NHEJ)
- DNA Double-Strand Break Repair
Biological Process
- single strand break repair
- in utero embryonic development
- pro-B cell differentiation
- DNA replication
- DNA ligation
Molecular Function
- DNA binding
- DNA ligase activity
- DNA ligase (ATP) activity
- protein binding
- ATP binding
Cellular Component
- nuclear chromosome, telomeric region
- condensed chromosome
- nucleus
- nucleoplasm
- DNA-dependent protein kinase-DNA ligase 4 complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000356922
- Coding exons
- 1
- Length
- 10930
- Individuals with no LoFs
- 125579
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 168
- Defined
- 125747
- p
- 0.000668
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.202 | 461 | 473 | 0.974 | 0.0000243 | 6070 |
| Missense (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 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0014 | 0.0014 | notable |
| Latino/Admixed American | 0.00067 | 0.00067 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.00079 | 0.00079 | rare |
| South Asian | 0.00059 | 0.00059 | rare |
| Other | 0.00082 | 0.00081 | rare |
dbNSFP Gene Annotations
Source:
- 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.;
Recessive Scores
- pRec
- 0.100
Intolerance Scores
- LoFtool
- 0.531
- RVIS EVS
- -0.39
- RVIS percentile EVS
- 27.05
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.700
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |