XRCC4

protein-coding

X-ray repair cross complementing 4

Gene summary

The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternate transcript variants such as NM_022406 are unlikely to be expressed in some individuals due to a polymorphism (rs1805377) in the last splice acceptor site. [provided by RefSeq, Oct 2019]

MANE transcript

NM_003401.5

Inheritance

ClinVar variants

P:23U:88B:36

Top phenotype

Short stature, microcephaly, and endocrine dysfunction

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr5:83,077,498-83,353,787

External References & Databases

Ensembl (ENSG00000152422)

Transcript & Mutation Effects

hg38 • Region Span ~276.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

short stature, microcephaly, and endocrine dysfunctionDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014686

Submitter: G2P

short stature, microcephaly, and endocrine dysfunctionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014686

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

short stature, microcephaly, and endocrine dysfunctionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014686

Submitter: PanelApp Australia

microcephalic primordial dwarfism-insulin resistance syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018575

Submitter: Orphanet

hereditary nonpolyposis colon cancerLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0018630

Submitter: ClinGen

short stature, microcephaly, and endocrine dysfunctionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014686

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Short stature, microcephaly, and endocrine dysfunctionAR

Manifestation: Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic; Oncologic; Renal

Intervention: Endocrine; Oncologic

Rationale: 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

Refs: 24389050; 25728776; 25742519; 25839420; 25872942; 26255102

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to XRCC4 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 113

Short stature, microcephaly, and endocrine dysfunctionTotal: 66

Inborn genetic diseasesTotal: 32

not specifiedTotal: 11

XRCC4-related disorderTotal: 7

Ateleiotic dwarfismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003401.5. 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				28 clinvar		28
missense	3 clinvar	2 clinvar	84 clinvar	6 clinvar	2 clinvar	97
nonsense	3 clinvar	4 clinvar	2 clinvar			9
start loss						0
frameshift	4 clinvar	4 clinvar	1 clinvar			9
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	1 clinvar			4
Total	11	12	88	34	2	147

Highest pathogenic variant AF is 0.00041716566

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_003401.5	RefSeq	NP_003392.1	7	MANE Select
ENST00000396027.9	Ensembl	ENSP00000379344.4	7	MANE Select
NM_001318012.3	RefSeq	NP_001304941.1	7	Standard
NM_001318013.2	RefSeq	NP_001304942.1	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
Disease
Nonhomologous End-Joining (NHEJ)

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

Molecular Function

DNA binding
protein binding
protein C-terminus binding
ligase activity
identical protein binding

Cellular Component

condensed chromosome
nucleus
nucleoplasm
cytosol
DNA-dependent protein kinase-DNA ligase 4 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000511817
Coding exons: 7
Length: 276290
Individuals with no LoFs: 125585
Homozygous LoFs: 0
Heterozygous LoFs: 141
Defined: 125726
p: 0.000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.298	152	163	0.934	0.00000748	2217
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00044	0.00043	rare
Latino/Admixed American	0.000088	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.00060	0.00060	rare
European (Non-Finnish)	0.00079	0.00079	rare
South Asian	0.00079	0.00078	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.288

Intolerance Scores

LoFtool: 0.972
RVIS EVS: 1.28
RVIS percentile EVS: 93.77

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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