XRCC4

X-ray repair cross complementing 4

Basic information

Region (hg38): 5:83077497-83353787

Links

ENSG00000152422 ∙ NCBI:7518 ∙ OMIM:194363 ∙ HGNC:12831 ∙ Uniprot:Q13426 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Fanconi anemia complementation group Q (Definitive), mode of inheritance: AR
• short stature, microcephaly, and endocrine dysfunction (Strong), mode of inheritance: AR
• short stature, microcephaly, and endocrine dysfunction (Strong), mode of inheritance: AR
• microcephalic primordial dwarfism-insulin resistance syndrome (Supportive), mode of inheritance: AR
• hereditary nonpolyposis colon cancer (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Short stature, microcephaly, and endocrine dysfunction	AR	Endocrine; Oncologic	Endocrine anomalies, including hypergonadotropic hypogonadism, multinodular goiter, and diabetes mellitus have been described, and awareness may allow screening and early management; The condition has been described as including an increased risk of cancer, and awareness may allow early detection and management	Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic; Oncologic; Renal	24389050; 25728776; 25742519; 25839420; 25872942; 26255102

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the XRCC4 gene.

• not provided (92 variants)
• Short stature, microcephaly, and endocrine dysfunction (22 variants)
• Inborn genetic diseases (9 variants)
• XRCC4-related condition (1 variants)
• Ateleiotic dwarfism (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the XRCC4 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				16	1	17
missense		1	40	3	5	49
nonsense		2	1			3
start loss						0
frameshift	5	3				8
inframe indel			1			1
splice donor/acceptor (+/-2bp)		1				1
splice region				5	2	7
non coding			1	9	8	18
Total	5	7	43	28	14

Highest pathogenic variant AF is 0.0000592

Variants in XRCC4

This is a list of pathogenic ClinVar variants found in the XRCC4 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-83104909-G-T		Short stature, microcephaly, and endocrine dysfunction	Pathogenic (Mar 05, 2015)
5-83104930-A-G		Inborn genetic diseases	Uncertain significance (Jan 30, 2024)
5-83104942-TC-T		Short stature, microcephaly, and endocrine dysfunction	Pathogenic/Likely pathogenic (Jan 12, 2024)
5-83104950-GT-G			Pathogenic (Jun 27, 2022)
5-83104954-C-G			Benign (Jan 23, 2024)
5-83104999-C-T		Short stature, microcephaly, and endocrine dysfunction	Uncertain significance (Jan 27, 2022)
5-83105045-A-G			Likely benign (Feb 11, 2022)
5-83105046-T-A		Short stature, microcephaly, and endocrine dysfunction	Pathogenic (-)
5-83105046-T-C		Ateleiotic dwarfism • Short stature, microcephaly, and endocrine dysfunction	Pathogenic/Likely pathogenic (Oct 23, 2020)
5-83105051-T-C			Likely benign (Mar 13, 2022)
5-83105065-C-T		Short stature, microcephaly, and endocrine dysfunction	Likely benign (Jan 24, 2023)
5-83105066-T-C			Likely benign (May 27, 2022)
5-83105076-G-C			Likely benign (Oct 22, 2023)
5-83105078-T-A			Likely benign (Feb 24, 2022)
5-83111013-T-C		Short stature, microcephaly, and endocrine dysfunction	Likely benign (Oct 05, 2023)
5-83111014-A-G			Likely benign (Dec 30, 2023)
5-83111015-A-G		Short stature, microcephaly, and endocrine dysfunction	Uncertain significance (-)
5-83111024-A-G		Short stature, microcephaly, and endocrine dysfunction • Inborn genetic diseases	Likely benign (Apr 28, 2023)
5-83111026-A-G		Short stature, microcephaly, and endocrine dysfunction	Likely pathogenic (Jan 29, 2024)
5-83111047-C-T			Likely benign (Apr 03, 2018)
5-83111054-G-A		Short stature, microcephaly, and endocrine dysfunction	Uncertain significance (Oct 13, 2022)
5-83111059-T-C			Likely benign (May 11, 2022)
5-83111066-GC-G			Pathogenic (Nov 08, 2022)
5-83111069-A-G			Uncertain significance (Aug 17, 2023)
5-83111070-T-C			Uncertain significance (Feb 19, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
XRCC4	protein_coding	protein_coding	ENST00000511817	7	276290

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.28e-7	0.755	125585	0	141	125726	0.000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.298	152	163	0.934	0.00000748	2217
Missense in Polyphen		92	91.454	1.006		1297
Synonymous	1.10	46	56.5	0.814	0.00000263	600
Loss of Function	1.27	12	17.8	0.675	0.00000111	213

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000525	0.000519
Ashkenazi Jewish	0.00	0.00
East Asian	0.000164	0.000163
Finnish	0.000601	0.000601
European (Non-Finnish)	0.000794	0.000792
Middle Eastern	0.000164	0.000163
South Asian	0.000793	0.000784
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. Binds to DNA and to DNA ligase IV (LIG4). 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:10757784, ECO:0000269|PubMed:10854421, ECO:0000269|PubMed:16412978, ECO:0000269|PubMed:8548796}.
• Disease: DISEASE: Short stature, microcephaly, and endocrine dysfunction (SSMED) [MIM:616541]: A disease characterized by short stature and microcephaly apparent at birth, progressive postnatal growth failure, and endocrine dysfunction. In affected adults endocrine features include hypergonadotropic hypogonadism, multinodular goiter, and diabetes mellitus. Variable features observed in some patients are progressive ataxia, and lymphopenia or borderline leukopenia. {ECO:0000269|PubMed:24389050, ECO:0000269|PubMed:25728776, ECO:0000269|PubMed:25839420, ECO:0000269|PubMed:26255102}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Non-homologous end-joining - Homo sapiens (human);Non-homologous end joining;DNA Repair;Disease;Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair;HIV Life Cycle;HIV Infection;SUMOylation of DNA damage response and repair proteins;2-LTR circle formation;Post-translational protein modification;SUMO E3 ligases SUMOylate target proteins;Metabolism of proteins;Infectious disease;SUMOylation;ATM pathway;DNA-PK pathway in nonhomologous end joining;Integration of provirus;Early Phase of HIV Life Cycle (Consensus)

Recessive Scores

• pRec: 0.288

Intolerance Scores

• loftool: 0.972
• rvis_EVS: 1.28
• rvis_percentile_EVS: 93.77

Haploinsufficiency Scores

• pHI: 0.799
• hipred: Y
• hipred_score: 0.672
• ghis: 0.425

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Xrcc4
• Phenotype: neoplasm; 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); reproductive system phenotype; hematopoietic 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); skeleton phenotype; cellular phenotype; immune system phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; craniofacial phenotype

Gene ontology

• Biological process: double-strand break repair;double-strand break repair via nonhomologous end joining;DNA recombination;response to X-ray;DNA ligation involved in DNA repair;positive regulation of ligase activity;cellular response to lithium ion;establishment of integrated proviral latency
• Cellular component: condensed chromosome;nucleus;nucleoplasm;cytosol;DNA-dependent protein kinase-DNA ligase 4 complex;DNA ligase IV complex;nonhomologous end joining complex
• Molecular function: DNA binding;protein binding;protein C-terminus binding;ligase activity;identical protein binding