LIG1

protein-coding

DNA ligase 1, the group of Nucleotide excision repair|DNA ligases

Gene summary

This gene encodes a member of the ATP-dependent DNA ligase protein family. The encoded protein functions in DNA replication, recombination, and the base excision repair process. Mutations in this gene that lead to DNA ligase I deficiency result in immunodeficiency and increased sensitivity to DNA-damaging agents. Disruption of this gene may also be associated with a variety of cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

MANE transcript

NM_000234.3

Inheritance

ClinVar variants

P:4U:316B:251

Top phenotype

Immunodeficiency 96

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr19:48,115,445-48,170,603

External References & Databases

Ensembl (ENSG00000105486)

Transcript & Mutation Effects

hg38 • Region Span ~55.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 96DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030693

Submitter: ClinGen

*LIG1* was first reported in relation to autosomal recessive immunodeficiency 96 in 1992 (Barnes et al., PMID: 1581963). *LIG1* encodes DNA ligase I, the primary enzyme responsible for sealing nicks in the DNA backbone during replication and repair. It plays a central role in multiple repair pathways including nucleotide excision repair, mismatch repair, and long-patch base excision repair. Deficiency of *LIG1* leads to a spectrum of clinical features including severe combined immunodeficiency (SCID), macrocytic anemia, growth delay, and recurrent infections. At least 13 unique variants (missense, frameshift, and splice-site) have been reported in 10 probands across 6 publications (PMIDs: 1581963, 30395541, 29682684, 36341401, 38896336, 40052222). The mechanism of disease is biallelic loss of function, supported by multiple lines of experimental evidence. Heterozygotes are not known to be clinically affected. Functional alteration in patient-derived fibroblasts demonstrated intermediate sensitivity to ionizing radiation, confirming impaired DNA repair capacity (PMID: 36341401). Additional patient cell studies showed reduced formation of the LIG1–AMP intermediate and impaired nick sealing (PMID: 1581963). In non-patient cells, engineered HEK293T lines expressing mutant alleles (R771W, R641L, E566K) revealed reduced ligation efficiency and accumulation of abortive ligation intermediates (PMID: 30395541). A mouse model expressing a patient variant showed replication defects, increased micronuclei, and tumor susceptibility (PMID: 12124343), while a knockout model was embryonically lethal (PMID: 8696349). Biochemical studies further confirmed that LIG1 dysfunction leads to accumulation of 5′-AMP–DNA and potential double-strand breaks, mechanisms relevant to immunodeficiency (PMID: 35790757). In summary, there is definitive evidence to support the relationship between *LIG1* and autosomal recessive immunodeficiency 96. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

immunodeficiency 96STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030693

Submitter: PanelApp Australia

immunodeficiency 96STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030693

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Immunodeficiency 96AR

Manifestation: Allergy/Immunology/Infectious; Hematologic

Intervention: Allergy/Immunology/Infectious; Hematologic

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections and hematologic anomalies may be beneficial; Individuals have been described as affected by hematolgic disturbances, such as anemia requiring RBC transfusions, and awareness may allow early diagnosis and medical management; HSCT has been described

Refs: 1351188; 1581963; 30395541

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LIG1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 742

not specifiedTotal: 199

LIG1-related disorderTotal: 25

Immunodeficiency 96Total: 19

DNA Ligase I DeficiencyTotal: 2

Permanent neonatal diabetes mellitusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000234.3. 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			6 clinvar	224 clinvar	5 clinvar	235
missense	1 clinvar	1 clinvar	288 clinvar	14 clinvar	8 clinvar	312
nonsense			7 clinvar			7
start loss			1 clinvar			1
frameshift	1 clinvar	1 clinvar	5 clinvar			7
splice donor/acceptor (+/-2bp)			9 clinvar			9
Total	2	2	316	238	13	571

Highest pathogenic variant AF is 0.00004774874

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 112 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000234.3	RefSeq	NP_000225.1	27	MANE Select
ENST00000263274.12	Ensembl	ENSP00000263274.6	27	MANE Select
NM_001289063.2	RefSeq	NP_001275992.1	26	Standard
NM_001289064.2	RefSeq	NP_001275993.1	25	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nucleotide excision repair - Homo sapiens (human)
Base excision repair - Homo sapiens (human)
Mismatch repair - Homo sapiens (human)
DNA replication - Homo sapiens (human)
Nucleotide Excision Repair

Biological Process

DNA ligation
lagging strand elongation
DNA repair
transcription-coupled nucleotide-excision repair
base-excision repair

Molecular Function

DNA binding
DNA ligase activity
DNA ligase (ATP) activity
ATP binding
metal ion binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
mitochondrion
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263274
Coding exons: 27
Length: 55159
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125748
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.820	512	567	0.903	0.0000388	5914
Missense (PolyPhen)		167	205.95	0.81088		2016
Synonymous	-0.696	253	239	1.06	0.0000175	1847
Loss of Function	4.61	14	48.7	0.288	0.00000222	594

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.00021	0.00021	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA ligase that seals nicks in double-stranded DNA during DNA replication, DNA recombination and DNA repair.;

Recessive Scores

pRec: 0.388

Intolerance Scores

LoFtool: 0.547
RVIS EVS: 0.37
RVIS percentile EVS: 74.73

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.982

Gene Damage Prediction

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