• 30
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
ERCC3 (HGNC:3435) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
ERCC excision repair 3, TFIIH core complex helicase subunit
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
XPB, BTF2, RAD25, Ssl2
%HI
16.21(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0(Read more about gnomAD pLI score)
LOEUF
0.79(Read more about gnomAD LOEUF score)
Cytoband
2q14.3
Genomic Coordinates
GRCh37/hg19: chr2:128014866-128051720 NCBI Ensembl UCSC
GRCh38/hg38: chr2:127257290-127294144 NCBI Ensembl UCSC
MANE Select Transcript
NM_000122.2 ENST00000285398.7 (Read more about MANE Select)
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 ac... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-26203
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Gene Associated with Autosomal Recessive Phenotype (30)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
06/30/2020

Haploinsufficiency (HI) Score Details

HI Score:
30
HI Evidence Strength:
Gene Associated with Autosomal Recessive Phenotype (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 27655433
    A truncating mutation c.325C>T:p.Arg109* (R109X) in exon 3 of ERCC3 was observed recurrently among exomes sequenced in BRCA negative, breast cancer-affected individuals of Ashkenazi Jewish ancestry. It was detected in three affected siblings from a family with multiple cancer affecters. The same variant was observed in two other individuals from an unrelated family with multiple cases of breast cancer. Modeling of the mutation in ERCC3 deficient or CRISPR/Cas9 edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair-deficient phenotype. Comparison of frequency of this recurrent mutation in over 6500 chromosomes of breast cancer cases and 6800 Ashkenazi controls showed significant association with breast cancer risk (ORBC=1.53, ORER+=1.73) particularly for the estrogen receptor positive (ER+) subset (P<0.007). However, the variant was observed in the gnomAD with a minor allele frequency of 0.92% (95/10370, 0 hom) in the Ashkenazi Jewish subpopulation. The MAFs in male and female in the overall population are similar (~0.49%).
  • PUBMED: 28202063
    Jalkh et al performed whole exome sequencing in 45 patients with a reported family history of breast cancer and identified a rare nonsense variant in exon 6 of ERCC3 (NM_000122.1): c.700C>T p.R234* in the family 3/patient B22 who was also found to carry multiple variants in different cancer predisposition genes (eg. BRCA2, TP53, VHL PTCH1); however, none of these variants can be classified as pathogenic or likely pathogenic. No segregation data is available. The association between ERCC3 and breast cancer cannot be established based on this study.
HI Evidence Comments:
Biallelic disease-causing variants in ERCC3 can cause autosomal recessive disorders Trichothiodystrophy 2, photosensitive (TTD) or Xeroderma pigmentosum, group B. Oh et al (2006) reported multiple patients from six families with biallelic disease-causing variants in the ERCC3 gene. Clinical features in these patients include Xeroderma Pigmentosum type B (XPB) with or without Cockayne syndrome and Trichothiodystrophy 2 (TTD). Functional assessment of patient-derived cells suggested all XPB cells had reduced nucleotide excision repair (NER) and post-UV cell viability. Cells from patients with missense variants displayed different levels of DNA repair and clinical features. Some missense variants produced a much less severe reduction of NER. They concluded that the remarkable phenotypic heterogeneity of XPB among these families was associated with different genotypes. Patients with milder phenotype carry partially active missense variants in one allele and a truncating variant in the other allele while severe patients have truncating variants in both alleles resulting in low levels of altered XPB protein. No symptoms were reported in parents or siblings who carry a heterozygous variant [PMID: 16947863]. Heterozygous truncating variants were reported in multiple individuals with different types of cancers including breast cancer, colorectal carcinoma, medulloblastoma et al, however, the evidence for this association is limited.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
At this time there is no evidence to support the triplosensitivity of this gene.

Genomic View

Select assembly: (NC_000002.11) (NC_000002.12)