NHEJ1

non-homologous end joining factor 1

Basic information

Region (hg38): 2:219069354-219160869

Links

ENSG00000187736 ∙ NCBI:79840 ∙ OMIM:611290 ∙ HGNC:25737 ∙ Uniprot:Q9H9Q4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Cernunnos-XLF deficiency (Supportive), mode of inheritance: AR
• Cernunnos-XLF deficiency (Strong), mode of inheritance: AR
• Cernunnos-XLF deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation	AR	Allergy/Immunology/Infectious	Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial	Allergy/Immunology/Infectious; Craniofacial; Musculoskeletal; Neurologic	12604777; 16439204; 16439205; 17191205; 20597108
Some individuals may not demonstrate obvious dysmorphic features

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NHEJ1 gene.

• Cernunnos-XLF deficiency (144 variants)
• not provided (54 variants)
• not specified (18 variants)
• Inborn genetic diseases (9 variants)
• Severe combined immunodeficiency with sensitivity to ionizing radiation due to NHEJ1 deficiency (1 variants)
• Isolated anophthalmia-microphthalmia syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NHEJ1 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			2	31	2	35
missense		1	70		3	74
nonsense	6		1			7
start loss						0
frameshift	6	1				7
inframe indel						0
splice donor/acceptor (+/-2bp)	1	7				8
splice region			3	6	1	10
non coding		1	1	19	29	50
Total	13	10	74	50	34

Variants in NHEJ1

This is a list of pathogenic ClinVar variants found in the NHEJ1 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-219076224-G-A			Benign (Oct 12, 2019)
2-219076341-G-A		not specified	Benign (Nov 12, 2023)
2-219076385-C-T		Cernunnos-XLF deficiency	Uncertain significance (Aug 26, 2021)
2-219076386-T-C		Cernunnos-XLF deficiency	Uncertain significance (Aug 24, 2023)
2-219076421-G-A		Cernunnos-XLF deficiency	Uncertain significance (Mar 20, 2022)
2-219076421-G-T		not specified	Uncertain significance (Feb 17, 2023)
2-219076439-A-G		Cernunnos-XLF deficiency	Uncertain significance (Jun 14, 2021)
2-219076439-A-T		Inborn genetic diseases	Uncertain significance (Oct 13, 2023)
2-219076444-G-T		Cernunnos-XLF deficiency	Likely benign (Dec 06, 2023)
2-219076447-T-G		Cernunnos-XLF deficiency	Likely benign (Aug 09, 2022)
2-219076451-G-A		Cernunnos-XLF deficiency	Uncertain significance (Apr 05, 2022)
2-219076468-G-A		Cernunnos-XLF deficiency	Benign (Jan 08, 2024)
2-219076505-G-A			Benign (Oct 12, 2019)
2-219076555-G-A			Benign (May 13, 2021)
2-219076557-CTTTTTTTTTT-C			Benign (May 13, 2021)
2-219076557-C-CT			Benign (Oct 28, 2019)
2-219076642-C-A			Benign (Oct 12, 2019)
2-219076956-T-C			Benign (Jun 17, 2019)
2-219077145-T-C			Benign (May 13, 2021)
2-219077217-C-T			Likely benign (Sep 05, 2018)
2-219077225-AG-A		Cernunnos-XLF deficiency	Likely benign (Jun 01, 2022)
2-219077243-C-T		Cernunnos-XLF deficiency	Uncertain significance (Nov 23, 2021)
2-219077253-T-G		Cernunnos-XLF deficiency	Uncertain significance (Jul 31, 2021)
2-219077265-G-A		not specified	Uncertain significance (Feb 18, 2022)
2-219077265-GC-AA		Cernunnos-XLF deficiency	Uncertain significance (Oct 05, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NHEJ1	protein_coding	protein_coding	ENST00000356853	7	85549

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00419	0.989	125735	0	13	125748	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0137	159	159	0.997	0.00000861	1943
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000181	0.000181
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000266	0.0000264
Middle Eastern	0.000109	0.000109
South Asian	0.0000653	0.0000653
Other	0.000163	0.000163

dbNSFP

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}.
• Pathway: Non-homologous end-joining - Homo sapiens (human);Non-homologous end joining;DNA Repair;Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair;DNA-PK pathway in nonhomologous end joining (Consensus)

Recessive Scores

• pRec: 0.0790

Intolerance Scores

• loftool: 0.549
• rvis_EVS: 0.04
• rvis_percentile_EVS: 57.15

Haploinsufficiency Scores

• pHI: 0.0759
• hipred: N
• hipred_score: 0.493

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.216

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nhej1
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; endocrine/exocrine gland 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); hematopoietic 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; embryo phenotype

Gene ontology

• Biological process: double-strand break repair via nonhomologous end joining;central nervous system development;response to ionizing radiation;B cell differentiation;T cell differentiation;positive regulation of ligase activity
• Cellular component: fibrillar center;nucleus;nucleoplasm;DNA ligase IV complex;nonhomologous end joining complex
• Molecular function: protein binding;DNA end binding