ERCC4

ERCC excision repair 4, endonuclease catalytic subunit, the group of Xeroderma pigmentosum complementation groups|FA complementation groups|ERCC excision repair associated

Basic information

Region (hg38): 16:13920138-13952348

Previous symbols: [ "XPF" ]

Links

ENSG00000175595 ∙ NCBI:2072 ∙ OMIM:133520 ∙ HGNC:3436 ∙ Uniprot:Q92889 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Fanconi anemia complementation group Q (Strong), mode of inheritance: AR
• xeroderma pigmentosum group F (Strong), mode of inheritance: AR
• Fanconi anemia complementation group Q (Moderate), mode of inheritance: AR
• XFE progeroid syndrome (Strong), mode of inheritance: AR
• Fanconi anemia (Supportive), mode of inheritance: AR
• xeroderma pigmentosum (Supportive), mode of inheritance: AR
• xeroderma pigmentosum-Cockayne syndrome complex (Supportive), mode of inheritance: AR
• Fanconi anemia complementation group Q (Strong), mode of inheritance: AR
• xeroderma pigmentosum group F (Definitive), mode of inheritance: AR
• xeroderma pigmentosum group F (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Fanconi anemia, complementation group Q; Xeroderma pigmentosum, complementation group F	AR	Cardiovascular; Dermatologic; Hematologic; Oncologic	In XP, skin lesions can be treated (and possibly prevented in some cases) with a variety of methods, depending on the specific type of lesion; Sun/UV exposure (and other agents, such as tobacco smoke) should be avoided; Periodic surveillance (primarily related to skin manifestations, as well as other sequelae) can be beneficial; In Fanconi anemia, specific treatments can help manifestations (eg, oral androgens for blood counts; G-CSF for neutrophil count), and awareness of potential cardiac anomalies may enable early identification and management; HSCT can be curative, but solid tumor risk may remain; Surveillance for complications such as bone marrow failure is recommended	Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Endocrine; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; Renal	3834095; 3372781; 2696553; 8427828; 10447254; 17183314; 20301571; 23623386

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ERCC4 gene.

• Xeroderma_pigmentosum,_group_F (666 variants)
• Fanconi_anemia_complementation_group_Q (653 variants)
• Cockayne_syndrome (616 variants)
• not_provided (156 variants)
• Inborn_genetic_diseases (101 variants)
• XFE_progeroid_syndrome (84 variants)
• not_specified (72 variants)
• Xeroderma_pigmentosum (56 variants)
• ERCC4-related_disorder (28 variants)
• Hereditary_cancer-predisposing_syndrome (8 variants)
• Ovarian_cancer (7 variants)
• Hutchinson-Gilford_syndrome (4 variants)
• Xeroderma_pigmentosum,_type_F/Cockayne_syndrome (3 variants)
• ERCC4-Related_Disorders (2 variants)
• Spastic_ataxia (2 variants)
• Microcephaly (1 variants)
• Carcinoma_of_pancreas (1 variants)
• Abnormality_of_blood_and_blood-forming_tissues (1 variants)
• Behavioral_variant_of_frontotemporal_dementia (1 variants)
• Breast_carcinoma (1 variants)
• Autosomal_recessive_cerebellar_ataxia (1 variants)
• Precursor_B-cell_acute_lymphoblastic_leukemia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ERCC4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000005236.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	181	2	189
missense	2	11	439	24	3	479
nonsense	15	7	3			25
start loss			4			4
frameshift	11	16	4			31
splice donor/acceptor (+/-2bp)	1	8	2			11
Total	29	42	458	205	5

Highest pathogenic variant AF is 0.0006288147

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ERCC4	protein_coding	protein_coding	ENST00000311895	11	32189

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.38e-12	0.924	125654	0	94	125748	0.000374

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.762	557	509	1.10	0.0000294	5982
Missense in Polyphen		172	161.71	1.0636		1892
Synonymous	-1.58	215	188	1.15	0.0000107	1792
Loss of Function	2.07	25	39.0	0.642	0.00000213	467

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000569	0.000568
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.000544	0.000544
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000362	0.000360
Middle Eastern	0.000544	0.000544
South Asian	0.000687	0.000686
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair. Involved in homologous recombination that assists in removing interstrand cross-link. {ECO:0000269|PubMed:19596235}.
• Disease: DISEASE: Xeroderma pigmentosum complementation group F (XP-F) [MIM:278760]: An autosomal recessive pigmentary skin disorder characterized by solar hypersensitivity of the skin, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities. The skin develops marked freckling and other pigmentation abnormalities. XP-F patients show a mild phenotype. {ECO:0000269|PubMed:10447254, ECO:0000269|PubMed:8797827, ECO:0000269|PubMed:9579555, ECO:0000269|PubMed:9580660}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: XFE progeroid syndrome (XFEPS) [MIM:610965]: A syndrome characterized by aged bird-like facies, lack of subcutaneous fat, dwarfism, cachexia and microcephaly. Additional features include sun-sensitivity from birth, learning disabilities, hearing loss, and visual impairment. {ECO:0000269|PubMed:17183314}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Xeroderma pigmentosum type F/Cockayne syndrome (XPF/CS) [MIM:278760]: A variant form of Cockayne syndrome, a disorder characterized by growth retardation, microcephaly, impairment of nervous system development, pigmentary retinopathy, peculiar facies, and progeria together with abnormal skin photosensitivity. Cockayne syndrome dermatological features are milder than those in xeroderma pigmentosum and skin cancers are not found in affected individuals. XPF/CS patients, however, present with severe skin phenotypes, including severe photosensitivity, abnormal skin pigmentation, and skin cancer predisposition. {ECO:0000269|PubMed:23623389}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Fanconi anemia complementation group Q (FANCQ) [MIM:615272]: A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. {ECO:0000269|PubMed:23623386, ECO:0000269|PubMed:24027083}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Fanconi anemia pathway - Homo sapiens (human);Nucleotide excision repair - Homo sapiens (human);Cyclophosphamide Pathway, Pharmacodynamics;Nucleotide Excision Repair ;HDR through Single Strand Annealing (SSA);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);Fanconi Anemia Pathway;DNA Repair;DNA Double-Strand Break Repair;Homology Directed Repair;Formation of Incision Complex in GG-NER;Dual Incision in GG-NER;Global Genome Nucleotide Excision Repair (GG-NER);Dual incision in TC-NER;Transcription-Coupled Nucleotide Excision Repair (TC-NER);Nucleotide Excision Repair (Consensus)

Recessive Scores

• pRec: 0.478

Intolerance Scores

• loftool: 0.878
• rvis_EVS: -0.37
• rvis_percentile_EVS: 28.29

Haploinsufficiency Scores

• pHI: 0.843
• hipred: N
• hipred_score: 0.498
• ghis: 0.562

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.952

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ercc4
• Phenotype: liver/biliary 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); cellular phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: resolution of meiotic recombination intermediates;telomere maintenance;double-strand break repair via homologous recombination;DNA repair;transcription-coupled nucleotide-excision repair;nucleotide-excision repair;nucleotide-excision repair, preincision complex stabilization;nucleotide-excision repair, DNA incision, 3'-to lesion;nucleotide-excision repair, DNA incision, 5'-to lesion;double-strand break repair via nonhomologous end joining;response to UV;UV protection;regulation of autophagy;negative regulation of telomere maintenance;nucleotide-excision repair, DNA incision;cellular response to UV;interstrand cross-link repair;negative regulation of telomerase activity;telomeric DNA-containing double minutes formation;global genome nucleotide-excision repair;nucleotide-excision repair involved in interstrand cross-link repair;negative regulation of telomere maintenance via telomere lengthening;negative regulation of protection from non-homologous end joining at telomere;negative regulation of double-stranded telomeric DNA binding
• Cellular component: nucleotide-excision repair complex;nucleotide-excision repair factor 1 complex;chromosome, telomeric region;nuclear chromosome, telomeric region;nucleus;nucleoplasm;transcription factor TFIID complex;ERCC4-ERCC1 complex
• Molecular function: single-stranded DNA endodeoxyribonuclease activity;TFIID-class transcription factor complex binding;DNA binding;damaged DNA binding;single-stranded DNA binding;endodeoxyribonuclease activity;protein binding;protein C-terminus binding;telomerase inhibitor activity;identical protein binding;protein N-terminus binding;3' overhang single-stranded DNA endodeoxyribonuclease activity