XPC

protein-coding

XPC complex subunit, DNA damage recognition and repair factor, the group of Xeroderma pigmentosum complementation groups

Gene summary

The protein encoded by this gene is a key component of the XPC complex, which plays an important role in the early steps of global genome nucleotide excision repair (NER). The encoded protein is important for damage sensing and DNA binding, and shows a preference for single-stranded DNA. Mutations in this gene or some other NER components can result in Xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

MANE transcript

NM_004628.5

Inheritance

ClinVar variants

P:238U:205B:427

Top phenotype

Xeroderma pigmentosum, group C

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr3:14,145,145-14,178,621

External References & Databases

Ensembl (ENSG00000154767)

Transcript & Mutation Effects

hg38 • Region Span ~33.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

xeroderma pigmentosum group CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010211

Submitter: Genomics England PanelApp

xeroderma pigmentosumSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019600

Submitter: Orphanet

xeroderma pigmentosum group CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010211

Submitter: Labcorp Genetics (formerly Invitae)

xeroderma pigmentosum group CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010211

Submitter: G2P

xeroderma pigmentosum group CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010211

Submitter: Myriad Women's Health

xeroderma pigmentosum group CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010211

Submitter: ClinGen

There is abundant evidence published associating the XPC gene with xeroderma pigmentosum group C since the gene-disease relationship was first proposed by Li et al. (1993). Multiple case level studies have been performed with XPC patients that have variants in the XPC 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 Xpc deficient mouse models have been established to show consistent phenotypes with XPC patients, including highly susceptible to ultraviolet-induced carcinogenesis and chemically-induced liver and lung tumors. All of these types of evidence are consistent with a definitive relationship between the XPC gene and xeroderma pigmentosum group C.

xeroderma pigmentosum group CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010211

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Xeroderma pigmentosum, group CAR

Manifestation: Dermatologic; Neurologic; Oncologic; Ophthalmologic

Intervention: Dermatologic; Oncologic; Ophthalmologic

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 (primarily related to skin manifestations, as well as other sequelae) can be beneficial

Refs: 7389185; 6696469; 8298653; 9804340; 10766188; 11511294; 14662655; 20301571; 21482201; 22211393; 23143338; 23173980; 23436679

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to XPC variants in ClinVar

12 Conditions Cataloged

not providedTotal: 859

Xeroderma pigmentosum, group CTotal: 290

Inborn genetic diseasesTotal: 94

not specifiedTotal: 83

Xeroderma pigmentosumTotal: 76

XPC-related disorderTotal: 35

Ovarian cancerTotal: 5

Xeroderma pigmentosum group ATotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004628.5. 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			4 clinvar	391 clinvar	4 clinvar	399
missense		4 clinvar	187 clinvar	27 clinvar	5 clinvar	223
nonsense	37 clinvar	20 clinvar	4 clinvar			61
start loss	2 clinvar	3 clinvar				5
frameshift	74 clinvar	44 clinvar	6 clinvar			124
splice donor/acceptor (+/-2bp)	13 clinvar	41 clinvar	4 clinvar			58
Total	126	112	205	418	9	870

Highest pathogenic variant AF is 0.000033959957

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004628.5	RefSeq	NP_004619.3	16	MANE Select
ENST00000285021.12	Ensembl	ENSP00000285021.8	16	MANE Select
NM_001354726.2	RefSeq	NP_001341655.1	12	Standard
NM_001354727.2	RefSeq	NP_001341656.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nucleotide excision repair - Homo sapiens (human)
DNA Repair
SUMOylation of DNA damage response and repair proteins
Post-translational protein modification
SUMO E3 ligases SUMOylate target proteins

Biological Process

nucleotide-excision repair, DNA damage recognition
DNA repair
nucleotide-excision repair
nucleotide-excision repair, preincision complex assembly
mismatch repair

Molecular Function

heteroduplex DNA loop binding
bubble DNA binding
damaged DNA binding
single-stranded DNA binding
protein binding

Cellular Component

nucleotide-excision repair complex
nucleotide-excision repair factor 2 complex
nucleus
nucleoplasm
nucleolus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000285021
Coding exons: 16
Length: 33637
Individuals with no LoFs: 124669
Homozygous LoFs: 0
Heterozygous LoFs: 86
Defined: 124755
p: 0.000345

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.695	483	528	0.915	0.0000304	6115
Missense (PolyPhen)		153	183.91	0.83194		2051
Synonymous	0.125	200	202	0.989	0.0000116	1846
Loss of Function	2.70	24	43.2	0.556	0.00000236	526

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00085	0.00084	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00080	0.00080	rare
East Asian	0.000056	0.000055	rare
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.00036	0.00034	rare
South Asian	0.00043	0.00042	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in global genome nucleotide excision repair (GG-NER) by acting as damage sensing and DNA-binding factor component of the XPC complex. Has only a low DNA repair activity by itself which is stimulated by RAD23B and RAD23A. Has a preference to bind DNA containing a short single-stranded segment but not to damaged oligonucleotides. This feature is proposed to be related to a dynamic sensor function: XPC can rapidly screen duplex DNA for non-hydrogen-bonded bases by forming a transient nucleoprotein intermediate complex which matures into a stable recognition complex through an intrinsic single-stranded DNA- binding activity.;
Disease: DISEASE: Xeroderma pigmentosum complementation group C (XP-C) [MIM:278720]: 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. {ECO:0000269|PubMed:10447254, ECO:0000269|PubMed:10766188, ECO:0000269|PubMed:17355181, ECO:0000269|PubMed:17682058, ECO:0000269|PubMed:19609301, ECO:0000269|PubMed:8298653}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.484

Intolerance Scores

LoFtool: 0.960
RVIS EVS: 0.45
RVIS percentile EVS: 78.04

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.808

Gene Damage Prediction

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