NHEJ1

protein-coding

non-homologous end joining factor 1

Gene summary

Double-strand breaks in DNA result from genotoxic stresses and are among the most damaging of DNA lesions. This gene encodes a DNA repair factor essential for the nonhomologous end-joining pathway, which preferentially mediates repair of double-stranded breaks. Mutations in this gene cause different kinds of severe combined immunodeficiency disorders. [provided by RefSeq, Jul 2008]

MANE transcript

NM_024782.3

Inheritance

ClinVar variants

P:38U:93B:68

Top phenotype

Immunodeficiency 124, severe combined

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr2:219,069,355-219,160,869

External References & Databases

Ensembl (ENSG00000187736)

Transcript & Mutation Effects

hg38 • Region Span ~91.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Cernunnos-XLF deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012650

Submitter: PanelApp Australia

Cernunnos-XLF deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012650

Submitter: ClinGen

NHEJ1 was first reported in relation to autosomal recessive Cernunnos-XLF deficiency in 2003 (Dai et al., PMID: 12604777). Cernunnos-XLF deficiency is a severe combined immunodeficiency (NHEJ1-SCID) characterized by profound T- and B-lymphocytopenia, microcephaly, growth retardation, and sensitivity to ionizing radiation. At least 9 unique variants (missense, nonsense, frameshift, small insertions, and gross deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data: 12.70 points. Variants in this gene have been reported in at least 13 probands in 6 publications (PMID: 16439204, PMID:12604777, PMID: 24511403, PMID: 20597108, PMID: 30666249, PMID: 28741180). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Summary of Experimental Evidence: 4.50 points. This gene-disease association is supported by animal models, rescue in patient cells, and protein interaction studies (PMID: 17360556, PMID: 16439205, PMID: 16439204). Using yeast two-hybrid screening and coimmunoprecipitation techniques, Ahnesorg P, et al. (2006), demonstrated that XLF directly interacts with the XRCC4-Ligase IV complex in vitro and in vivo and that siRNA-mediated downregulation of XLF in human cell lines leads to radiosensitivity and impaired NHEJ. Zha S, et al. (2007) used gene-targeted mutation to delete exons 4 and 5 from both copies of the Cernunnos-XLF gene in mouse ES cells. Analyses of these ES cells showed they produce no readily detectable Cernunnos-XLF protein, are highly sensitive to ionizing radiation, and have intrinsic DNA DSB repair defects. Additionally, the Cernunnos-XLF mutations led to increased spontaneous genomic instability, including translocations. In summary, there is definitive evidence to support the relationship between NHEJ1 and autosomal recessive Cernunnos-XLF deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date May 20, 2021 (SOP Version 8).

Cernunnos-XLF deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012650

Submitter: Orphanet

Cernunnos-XLF deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012650

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Immunodeficiency 124, severe combinedAR

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Comments: Microphthalmia/coloboma 13 involves an enhancer for IHH located within the NHEJ1 gene

Refs: 12604777; 16439204; 16439205; 17191205; 20597108; 37580330

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NHEJ1 variants in ClinVar

9 Conditions Cataloged

Cernunnos-XLF deficiencyTotal: 202

not providedTotal: 43

Inborn genetic diseasesTotal: 33

not specifiedTotal: 31

NHEJ1-related disorderTotal: 4

Microphthalmia/coloboma 13Total: 2

NHEJ1-related disordersTotal: 1

Severe combined immunodeficiency diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024782.3. 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			3 clinvar	60 clinvar		63
missense	2 clinvar	4 clinvar	88 clinvar	8 clinvar		102
nonsense	9 clinvar	1 clinvar	2 clinvar			12
start loss		1 clinvar				1
frameshift	10 clinvar	2 clinvar				12
splice donor/acceptor (+/-2bp)	2 clinvar	7 clinvar				9
Total	23	15	93	68	0	199

Highest pathogenic variant AF is 0.000016109205

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024782.3	RefSeq	NP_079058.1	7	MANE Select
ENST00000356853.10	Ensembl	ENSP00000349313.5	7	MANE Select
NM_001377498.1	RefSeq	NP_001364427.1	7	Standard
NM_001377499.1	RefSeq	NP_001364428.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Non-homologous end-joining - Homo sapiens (human)
Non-homologous end joining
DNA Repair
Nonhomologous End-Joining (NHEJ)
DNA Double-Strand Break Repair

Biological Process

double-strand break repair via nonhomologous end joining
central nervous system development
response to ionizing radiation
B cell differentiation
T cell differentiation

Molecular Function

protein binding
DNA end binding

Cellular Component

fibrillar center
nucleus
nucleoplasm
DNA ligase IV complex
nonhomologous end joining complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356853
Coding exons: 7
Length: 85549
Individuals with no LoFs: 125735
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125748
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0137	159	159	0.997	0.00000861	1943
Missense (PolyPhen)		42	49.415	0.84994		625
Synonymous	-1.39	76	62.1	1.22	0.00000339	587
Loss of Function	2.37	7	17.8	0.393	9.83e-7	180

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA repair protein involved in DNA nonhomologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. May serve as a bridge between XRCC4 and the other NHEJ factors located at DNA ends, or may participate in reconfiguration of the end bound NHEJ factors to allow XRCC4 access to the DNA termini. It may act in concert with XRCC6/XRCC5 (Ku) to stimulate XRCC4-mediated joining of blunt ends and several types of mismatched ends that are noncomplementary or partially complementary (PubMed:16439204, PubMed:16439205, PubMed:17470781). Binds DNA in a length-dependent manner (PubMed:17317666). {ECO:0000269|PubMed:16439204, ECO:0000269|PubMed:16439205, ECO:0000269|PubMed:17317666, ECO:0000269|PubMed:17470781}.;
Disease: DISEASE: Severe combined immunodeficiency due to NHEJ1 deficiency (NHEJ1-SCID) [MIM:611291]: SCID refers to 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 with SCID 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. NHEJ1-SCID is characterized by a profound T- and B-lymphocytopenia associated with increased cellular sensitivity to ionizing radiation, microcephaly and growth retardation. Some patients may manifest SCID with sensitivity to ionizing radiation without microcephaly and mild growth retardation, probably due to hypomorphic NHEJ1 mutations. {ECO:0000269|PubMed:16439204, ECO:0000269|PubMed:16439205, ECO:0000269|PubMed:17317666}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving NHEJ1 is found in a patient with polymicrogyria. Translocation t(2;7)(q35;p22). {ECO:0000269|PubMed:12604777}.;

Recessive Scores

pRec: 0.0790

Intolerance Scores

LoFtool: 0.549
RVIS EVS: 0.04
RVIS percentile EVS: 57.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.216

Gene Damage Prediction

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