ERCC3

ERCC excision repair 3, TFIIH core complex helicase subunit, the group of Xeroderma pigmentosum complementation groups|DNA helicases|ERCC excision repair associated|General transcription factor IIH complex subunits

Basic information

Region (hg38): 2:127257290-127294166

Links

ENSG00000163161 ∙ NCBI:2071 ∙ OMIM:133510 ∙ HGNC:3435 ∙ Uniprot:P19447 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• xeroderma pigmentosum group B (Definitive), mode of inheritance: AR
• xeroderma pigmentosum group B (Strong), mode of inheritance: AR
• trichothiodystrophy 1, photosensitive (Strong), mode of inheritance: AR
• xeroderma pigmentosum group B (Strong), mode of inheritance: AR
• xeroderma pigmentosum (Supportive), mode of inheritance: AR
• trichothiodystrophy (Supportive), mode of inheritance: AR
• xeroderma pigmentosum-Cockayne syndrome complex (Supportive), mode of inheritance: AR
• trichothiodystrophy 2, photosensitive (Limited), mode of inheritance: AR
• xeroderma pigmentosum group B (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Xeroderma pigmentosum, complementation group B; Trichothiodystrophy 2, photosensitive	AR	Allergy/Immunology/Infectious; Dermatologic; Oncologic	In Trichothiodystrophy, individuals may be at high risk for skin cancer, and preventive measures may be beneficial; Frequent infections have been reported, and prophylaxis and early and aggressive treatment of infections may be beneficial; 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	Allergy/Immunology/Infectious; Dermatologic; Endocrine; Genitourinary; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic	4811796; 6185841; 2189905; 2167179; 8783572; 9012405; 16947863; 20301571

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ERCC3 gene.

• not provided (26 variants)
• Xeroderma pigmentosum group B (6 variants)
• Xeroderma pigmentosum (2 variants)
• Trichothiodystrophy 2, photosensitive (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ERCC3 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			4	119	2	125
missense		1	198	2	4	205
nonsense	12	8				20
start loss						0
frameshift	14	2	2			18
inframe indel			7			7
splice donor/acceptor (+/-2bp)	1	3				4
splice region			11	19	1	31
non coding			7	64	29	100
Total	27	14	218	185	35

Highest pathogenic variant AF is 0.0000197

Variants in ERCC3

This is a list of pathogenic ClinVar variants found in the ERCC3 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-127257337-C-T		Xeroderma pigmentosum group B	Benign (Jan 10, 2019)
2-127257353-A-AT		Xeroderma pigmentosum	Uncertain significance (Jun 14, 2016)
2-127257376-C-G		Xeroderma pigmentosum group B	Uncertain significance (Jan 12, 2018)
2-127257419-T-C		Xeroderma pigmentosum group B	Benign (Jan 12, 2018)
2-127257458-C-G		Xeroderma pigmentosum group B	Uncertain significance (Jan 12, 2018)
2-127257490-A-G		Xeroderma pigmentosum group B	Likely benign (Jun 21, 2019)
2-127257513-G-A		Xeroderma pigmentosum group B	Uncertain significance (Jan 15, 2018)
2-127257567-G-A		Xeroderma pigmentosum group B	Benign/Likely benign (May 01, 2023)
2-127257609-C-T			Uncertain significance (Nov 26, 2021)
2-127257611-C-T		Xeroderma pigmentosum	Likely benign (Dec 28, 2023)
2-127257620-C-T			Likely benign (Jan 08, 2024)
2-127257639-G-A			Uncertain significance (Dec 02, 2021)
2-127257640-G-T			Uncertain significance (Jul 28, 2022)
2-127257641-C-T			Likely benign (Aug 19, 2022)
2-127257642-G-A		not specified	Uncertain significance (Sep 01, 2021)
2-127257642-G-C			Uncertain significance (Jun 10, 2022)
2-127257651-C-T			Uncertain significance (Oct 15, 2023)
2-127257652-G-A			Uncertain significance (Sep 01, 2022)
2-127257653-C-T			Likely benign (Apr 20, 2023)
2-127257659-G-C			Uncertain significance (Feb 24, 2021)
2-127257660-T-C		Inborn genetic diseases	Uncertain significance (Jul 18, 2022)
2-127257661-GGTACTCCAT-G		Xeroderma pigmentosum group B	Uncertain significance (-)
2-127257675-A-T			Uncertain significance (Sep 10, 2021)
2-127257682-C-T		not specified	Uncertain significance (Aug 24, 2022)
2-127257683-G-A			Likely benign (Jan 31, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ERCC3	protein_coding	protein_coding	ENST00000285398	15	36887

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.43e-11	0.996	125454	0	294	125748	0.00117

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.932	379	434	0.874	0.0000258	5165
Missense in Polyphen		123	162.77	0.75566		1937
Synonymous	0.328	164	169	0.968	0.0000106	1483
Loss of Function	2.68	24	43.0	0.559	0.00000276	463

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00152	0.00152
Ashkenazi Jewish	0.00913	0.00917
East Asian	0.000435	0.000435
Finnish	0.000185	0.000185
European (Non-Finnish)	0.00111	0.00111
Middle Eastern	0.000435	0.000435
South Asian	0.000523	0.000523
Other	0.00147	0.00147

dbNSFP

Source: dbNSFP

• Function: FUNCTION: ATP-dependent 3'-5' DNA helicase, component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. The ATPase activity of XPB/ERCC3, but not its helicase activity, is required for DNA opening. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. The ATP- dependent helicase activity of XPB/ERCC3 is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. {ECO:0000269|PubMed:10024882, ECO:0000269|PubMed:8157004}.
• Disease: DISEASE: Xeroderma pigmentosum complementation group B (XP-B) [MIM:610651]: 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. Some XP-B patients present features of Cockayne syndrome, including cachectic dwarfism, pigmentary retinopathy, ataxia, decreased nerve conduction velocities. The phenotype combining xeroderma pigmentosum and Cockayne syndrome traits is referred to as XP-CS complex. {ECO:0000269|PubMed:10447254, ECO:0000269|PubMed:16947863, ECO:0000269|PubMed:8304337}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Trichothiodystrophy 2, photosensitive (TTD2) [MIM:616390]: A form of trichothiodystrophy, an autosomal recessive disease characterized by sulfur-deficient brittle hair and multisystem variable abnormalities. The spectrum of clinical features varies from mild disease with only hair involvement to severe disease with cutaneous, neurologic and profound developmental defects. Ichthyosis, intellectual and developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections are common manifestations. There are both photosensitive and non- photosensitive forms of the disorder. {ECO:0000269|PubMed:9012405}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Nucleotide excision repair - Homo sapiens (human);Basal transcription factors - Homo sapiens (human);Eukaryotic Transcription Initiation;DNA Repair;Disease;RNA Pol II CTD phosphorylation and interaction with CE during HIV infection;NoRC negatively regulates rRNA expression;Negative epigenetic regulation of rRNA expression;Formation of the HIV-1 Early Elongation Complex;Epigenetic regulation of gene expression;Gene expression (Transcription);Formation of HIV-1 elongation complex containing HIV-1 Tat;Tat-mediated elongation of the HIV-1 transcript;HIV Transcription Elongation;Formation of HIV elongation complex in the absence of HIV Tat;Generic Transcription Pathway;Transcription of the HIV genome;Late Phase of HIV Life Cycle;HIV Life Cycle;HIV Infection;RNA Polymerase II HIV Promoter Escape;RNA Polymerase II Pre-transcription Events;RNA Polymerase II Transcription Initiation;RNA Polymerase II Transcription Initiation And Promoter Clearance;RNA Pol II CTD phosphorylation and interaction with CE;Formation of RNA Pol II elongation complex ;RNA Polymerase I Promoter Clearance;HIV Transcription Initiation;RNA Polymerase II Transcription;Metabolism of RNA;Infectious disease;RNA Polymerase I Transcription Termination;RNA Polymerase I Transcription;RNA Polymerase II Transcription Elongation;RNA Polymerase I Transcription Initiation;RNA Polymerase I Promoter Escape;RNA Polymerase II Promoter Escape;RNA Polymerase I Chain Elongation;AndrogenReceptor;RNA Polymerase II Transcription Pre-Initiation And Promoter Opening;TP53 Regulates Transcription of DNA Repair Genes;Transcriptional Regulation by TP53;mRNA Capping;Formation of the Early Elongation Complex;Formation of Incision Complex in GG-NER;Dual Incision in GG-NER;Global Genome Nucleotide Excision Repair (GG-NER);Formation of TC-NER Pre-Incision Complex;Dual incision in TC-NER;Gap-filling DNA repair synthesis and ligation in TC-NER;Transcription-Coupled Nucleotide Excision Repair (TC-NER);Nucleotide Excision Repair (Consensus)

Recessive Scores

• pRec: 0.268

Intolerance Scores

• loftool: 0.842
• rvis_EVS: -1.28
• rvis_percentile_EVS: 5.11

Haploinsufficiency Scores

• pHI: 0.724
• hipred: Y
• hipred_score: 0.715
• ghis: 0.651

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.927

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ercc3
• Phenotype: craniofacial phenotype; muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; growth/size/body region 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); 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); reproductive system phenotype; vision/eye phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: nucleotide-excision repair, DNA duplex unwinding;response to hypoxia;DNA topological change;DNA repair;transcription-coupled nucleotide-excision repair;nucleotide-excision repair;nucleotide-excision repair, preincision complex stabilization;nucleotide-excision repair, preincision complex assembly;nucleotide-excision repair, DNA incision, 5'-to lesion;transcription initiation from RNA polymerase I promoter;termination of RNA polymerase I transcription;transcription by RNA polymerase II;transcription initiation from RNA polymerase II promoter;transcription elongation from RNA polymerase II promoter;7-methylguanosine mRNA capping;apoptotic process;response to oxidative stress;protein localization;response to UV;UV protection;viral process;nucleotide-excision repair, DNA incision;hair cell differentiation;positive regulation of apoptotic process;positive regulation of transcription by RNA polymerase II;embryonic organ development;global genome nucleotide-excision repair;regulation of mitotic cell cycle phase transition
• Cellular component: nucleotide-excision repair factor 3 complex;transcription factor TFIIH core complex;nucleus;nucleoplasm;transcription factor TFIID complex;transcription factor TFIIH holo complex;transcriptional preinitiation complex
• Molecular function: DNA binding;damaged DNA binding;ATP-dependent DNA helicase activity;helicase activity;protein kinase activity;protein binding;ATP binding;protein C-terminus binding;DNA-dependent ATPase activity;transcription factor binding;RNA polymerase II CTD heptapeptide repeat kinase activity;ATPase activity;3'-5' DNA helicase activity;protein N-terminus binding