GeneBe

ERCC5

protein-coding

ERCC excision repair 5, endonuclease, the group of ERCC excision repair associated|Xeroderma pigmentosum complementation groups

Gene summary

This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]

Previous symbols:
  • ERCM2
  • XPGC

MANE transcript

NM_000123.4

Inheritance

AR

ClinVar variants

P:84U:186B:165

Top phenotype

Xeroderma pigmentosum, complementation group G; Xeroderma pigmentosum, complementation group G/Cockayne syndrome

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr13:102,845,831-102,875,995

External References & Databases

Ensembl (ENSG00000134899)NCBI Gene (2073)OMIM (133530)HGNC:3437GenCCUniProt (P28715)AlphaFoldClinVar (ERCC5)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~30.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

xeroderma pigmentosum group GDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010216

Submitter: Ambry Genetics

cerebrooculofacioskeletal syndrome 3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014696

Submitter: Ambry Genetics

xeroderma pigmentosum group GSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010216

Submitter: Labcorp Genetics (formerly Invitae)

xeroderma pigmentosum group GSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010216

Submitter: Genomics England PanelApp

xeroderma pigmentosumSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019600

Submitter: Orphanet

xeroderma pigmentosum-Cockayne syndrome complexSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016354

Submitter: Orphanet

xeroderma pigmentosum group GSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010216

Submitter: PanelApp Australia

cerebrooculofacioskeletal syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014696

Submitter: Labcorp Genetics (formerly Invitae)

xeroderma pigmentosum group GDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010216

Submitter: G2P

xeroderma pigmentosum group GDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010216

Submitter: ClinGen

There is abundant evidence published associating the ERCC5 gene with xeroderma pigmentosum group G since the gene-disease relationship was first proposed by Nouspikel and Clarkson (1994). Multiple case level studies have been performed with XPG patients that have variants in the ERCC5 gene. 8 complementation groups genes (XPA, XPB, XPC, XPD, XPE, XPF, XPG, and XP variant (XPV)) in Nucleotide excision repair (NER) pathway were reported to cause Xeroderma Pigmentosum. Multiple xpg deficient mouse models have been established to show consistent phenotypes with XPG patients, including growth retardation, short life span and highly sensitive to UV light. All of these types of All of these types of evidence are consistent with a definitive relationship between the ERCC5 gene and xeroderma pigmentosum group G.

COFS syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008926

Submitter: Orphanet

Clinical Genomic Database (CGD)

Xeroderma pigmentosum, complementation group G; Xeroderma pigmentosum, complementation group G/Cockayne syndromeAR

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic

Intervention: Dermatologic; Oncologic

Rationale: 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 for dermatologic manifestations can be beneficial

Refs: 492197; 11219864; 3620347; 8317483; 8818951; 9096355; 11228268; 11841555; 20301571; 24700531Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ERCC5 variants in ClinVar

22 Conditions Cataloged
not providedTotal: 319
Xeroderma pigmentosum, group GTotal: 143
not specifiedTotal: 83
Hereditary cancer-predisposing syndromeTotal: 72
Cerebrooculofacioskeletal syndrome 3Total: 70
Inborn genetic diseasesTotal: 34
ERCC5-related disorderTotal: 22
Xeroderma pigmentosumTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000123.4. 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.

EffectPLPVUSLBBSum
synonymous
7
clinvar
121
clinvar
4
clinvar
 132
missense
4
clinvar
12
clinvar
173
clinvar
37
clinvar
3
clinvar
 229
nonsense
11
clinvar
10
clinvar
1
clinvar
 22
start loss
0
frameshift
20
clinvar
20
clinvar
5
clinvar
 45
splice donor/acceptor (+/-2bp)
1
clinvar
6
clinvar
 7
Total36481861587435

Highest pathogenic variant AF is 0.00006260941

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000123.4RefSeqNP_000114.315MANE Select
ENST00000652225.2EnsemblENSP00000498881.215MANE Select
ENST00000472151.1EnsemblENSP00000436083.13Standard
ENST00000651002.1EnsemblENSP00000498809.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Nucleotide excision repair - Homo sapiens (human)
  • Nucleotide Excision Repair
  • DNA Repair
  • Formation of Incision Complex in GG-NER
  • Dual Incision in GG-NER

Biological Process

  • 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, 3'-to lesion

Molecular Function

  • bubble DNA binding
  • RNA polymerase II complex binding
  • double-stranded DNA binding
  • single-stranded DNA binding
  • endodeoxyribonuclease activity

Cellular Component

  • nucleotide-excision repair complex
  • nucleus
  • nucleoplasm
  • DNA replication factor A complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000355739
Coding exons
15
Length
31152
Individuals with no LoFs
125698
Homozygous LoFs
0
Heterozygous LoFs
50
Defined
125748
p
0.000199
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.1186286360.9870.00003597798
Missense (PolyPhen)2202250.977792766
Synonymous-0.1512512481.010.00001572258
Loss of Function2.642847.70.5870.00000243580

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000190.00018rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish00.0absent
East Asian0.000270.00027rare
Finnish00.0absent
European (Non-Finnish)0.000170.00017rare
South Asian0.000620.00062rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Single-stranded structure-specific DNA endonuclease involved in DNA excision repair. Makes the 3'incision in DNA nucleotide excision repair (NER). Acts as a cofactor for a DNA glycosylase that removes oxidized pyrimidines from DNA. May also be involved in transcription-coupled repair of this kind of damage, in transcription by RNA polymerase II, and perhaps in other processes too.;
Disease
DISEASE: Xeroderma pigmentosum complementation group G (XP-G) [MIM:278780]: 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-G patients present features of Cockayne syndrome, 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:11228268, ECO:0000269|PubMed:11841555, ECO:0000269|PubMed:12060391, ECO:0000269|PubMed:23255472, ECO:0000269|PubMed:7951246, ECO:0000269|PubMed:9096355}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cerebro-oculo-facio-skeletal syndrome 3 (COFS3) [MIM:616570]: 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:24700531}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.493

Intolerance Scores

LoFtool
0.898
RVIS EVS
0.55
RVIS percentile EVS
81.13

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.843

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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