ERCC1

protein-coding

ERCC excision repair 1, endonuclease non-catalytic subunit, the group of ERCC excision repair associated

Gene summary

The product of this gene functions in the nucleotide excision repair pathway, and is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. The encoded protein forms a heterodimer with the XPF endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5' incision in the process of excising the DNA lesion. The heterodimeric endonuclease is also involved in recombinational DNA repair and in the repair of inter-strand crosslinks. Mutations in this gene result in cerebrooculofacioskeletal syndrome, and polymorphisms that alter expression of this gene may play a role in carcinogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. The last exon of this gene overlaps with the CD3e molecule, epsilon associated protein gene on the opposite strand. [provided by RefSeq, Oct 2009]

MANE transcript

NM_001983.4

Inheritance

ClinVar variants

P:16U:50B:38

Top phenotype

Cerebrooculofacioskeletal syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr19:45,407,334-45,478,828

External References & Databases

Ensembl (ENSG00000012061)

Transcript & Mutation Effects

hg38 • Region Span ~71.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

COFS syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008926

Submitter: Orphanet

cerebrooculofacioskeletal syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012554

Submitter: PanelApp Australia

cerebrooculofacioskeletal syndrome 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012554

Submitter: G2P

cerebrooculofacioskeletal syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012554

Submitter: Genomics England PanelApp

cerebrooculofacioskeletal syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012554

Submitter: Labcorp Genetics (formerly Invitae)

cerebrooculofacioskeletal syndrome 4LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012554

Submitter: Ambry Genetics

Cockayne syndrome type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019570

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cerebrooculofacioskeletal syndrome 4AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 17273966; 23623389

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ERCC1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 134

not specifiedTotal: 30

Cerebrooculofacioskeletal syndrome 4Total: 15

ERCC1-related disorderTotal: 9

ERCC1-related disordersTotal: 3

Cutaneous photosensitivityTotal: 2

Premature ovarian insufficiencyTotal: 2

Cholestatic liver diseaseTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001983.4. 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			1 clinvar	34 clinvar	1 clinvar	36
missense	2 clinvar		46 clinvar	3 clinvar		51
nonsense	4 clinvar	3 clinvar	1 clinvar			8
start loss						0
frameshift		2 clinvar				2
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	2 clinvar			7
Total	8	8	50	37	1	104

Highest pathogenic variant AF is 0.00012764137

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 187 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001983.4	RefSeq	NP_001974.1	9	MANE Select
ENST00000300853.8	Ensembl	ENSP00000300853.3	9	MANE Select
NM_001166049.2	RefSeq	NP_001159521.1	8	Standard
NM_001369408.1	RefSeq	NP_001356337.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fanconi anemia pathway - Homo sapiens (human)
Nucleotide excision repair - Homo sapiens (human)
Cyclophosphamide Pathway, Pharmacodynamics
HDR through Single Strand Annealing (SSA)
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)

Biological Process

meiotic mismatch repair
pyrimidine dimer repair by nucleotide-excision repair
replicative cell aging
DNA repair
transcription-coupled nucleotide-excision repair

Molecular Function

single-stranded DNA endodeoxyribonuclease activity
TFIID-class transcription factor complex binding
DNA binding
damaged DNA binding
single-stranded DNA binding

Cellular Component

nucleotide-excision repair complex
nucleotide-excision repair factor 1 complex
nuclear chromosome, telomeric region
nucleoplasm
transcription factor TFIID complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000013807
Coding exons: 8
Length: 71496
Individuals with no LoFs: 125724
Homozygous LoFs: 0
Heterozygous LoFs: 24
Defined: 125748
p: 0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.664	165	191	0.865	0.0000115	2056
Missense (PolyPhen)		35	52.338	0.66872		554
Synonymous	-0.320	88	84.3	1.04	0.00000546	658
Loss of Function	0.717	12	15.0	0.800	7.25e-7	170

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000097	0.000097	rare
South Asian	0.00016	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 1: Non-catalytic component of a structure- specific DNA repair endonuclease responsible for the 5'-incision during DNA repair. Responsible, in conjunction with SLX4, for the first step in the repair of interstrand cross-links (ICL). Participates in the processing of anaphase bridge-generating DNA structures, which consist in incompletely processed DNA lesions arising during S or G2 phase, and can result in cytokinesis failure. Also required for homology-directed repair (HDR) of DNA double-strand breaks, in conjunction with SLX4.;
Disease: DISEASE: Cerebro-oculo-facio-skeletal syndrome 4 (COFS4) [MIM:610758]: A disorder of prenatal onset characterized by microcephaly, congenital cataracts, facial dysmorphism, neurogenic arthrogryposis, growth failure and severe psychomotor retardation. COFS is considered to be part of the nucleotide-excision repair disorders spectrum that include also xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome. {ECO:0000269|PubMed:17273966, ECO:0000269|PubMed:23623389}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.708

Intolerance Scores

LoFtool: 0.861
RVIS EVS: -0.36
RVIS percentile EVS: 29.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.918

Gene Damage Prediction

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