XPA
protein-codingXPA, DNA damage recognition and repair factor, the group of Xeroderma pigmentosum complementation groups
Gene summary
This gene encodes a zinc finger protein plays a central role in nucleotide excision repair (NER), a specialized type of DNA repair. NER is responsible for repair of UV radiation-induced photoproducts and DNA adducts induced by chemical carcinogens and chemotherapeutic drugs. The encoded protein interacts with DNA and several NER proteins, acting as a scaffold to assemble the NER incision complex at sites of DNA damage. Mutations in this gene cause Xeroderma pigmentosum complementation group A (XP-A), an autosomal recessive skin disorder featuring hypersensitivity to sunlight and increased risk for skin cancer. [provided by RefSeq, Aug 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~22.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0010210
Submitter: ClinGen
There is abundant evidence published associating the XPA gene with xeroderma pigmentosum group A since the gene-disease relationship was first proposed by Tanaka et al. (1990). Multiple case level studies have been performed with XPA patients that have variants in the XPA 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 Xpa deficient mouse models have been established to show consistent phenotypes with XPA patients, including growth retardation, abnormal behavior, premature aging and UV or chemical induced skin tumours. All of these types of evidence are consistent with a definitive relationship between the XPA gene and xeroderma pigmentosum group A.
Inheritance Pattern: AR
Disease ID:MONDO:0010210
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0010210
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0010210
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010210
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0019600
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0010210
Submitter: Myriad Women's Health
Clinical Genomic Database (CGD)
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to XPA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000380.4. 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 | 3 | 111 | 114 | |||
| missense | 10 | 61 | 8 | 1 | 80 | |
| nonsense | 17 | 11 | 1 | 29 | ||
| start loss | 1 | 3 | 1 | 5 | ||
| frameshift | 35 | 30 | 3 | 68 | ||
| splice donor/acceptor (+/-2bp) | 6 | 13 | 1 | 20 | ||
| Total | 59 | 67 | 70 | 119 | 1 | 316 |
Highest pathogenic variant AF is 0.00016981486
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000371.1 | 6 | MANE Select | |
| Ensembl | ENSP00000364270.5 | 6 | MANE Select | |
| RefSeq | NP_001341904.1 | 6 | Standard | |
| Ensembl | ENSP00000433006.1 | 6 | Standard |
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
- nucleotide-excision repair, DNA damage recognition
- DNA repair
- transcription-coupled nucleotide-excision repair
- base-excision repair
- nucleotide-excision repair, preincision complex stabilization
Molecular Function
- damaged DNA binding
- protein binding
- protein domain specific binding
- protein homodimerization activity
- metal ion binding
Cellular Component
- nucleotide-excision repair factor 1 complex
- nucleus
- nucleoplasm
- DNA replication factor A complex
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000375128
- Coding exons
- 6
- Length
- 22449
- Individuals with no LoFs
- 125614
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 128
- Defined
- 125742
- p
- 0.000509
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.346 | 139 | 151 | 0.921 | 0.00000731 | 1783 |
| Missense (PolyPhen) | 29 | 33.528 | 0.86495 | 415 | ||
| Synonymous | -0.444 | 57 | 52.9 | 1.08 | 0.00000262 | 484 |
| Loss of Function | 1.65 | 9 | 16.2 | 0.557 | 9.39e-7 | 185 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00043 | 0.00043 | rare |
| Latino/Admixed American | 0.00014 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00028 | 0.00027 | rare |
| Finnish | 0.0030 | 0.0030 | notable |
| European (Non-Finnish) | 0.00030 | 0.00030 | rare |
| South Asian | 0.00036 | 0.00036 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in DNA excision repair. Initiates repair by binding to damaged sites with various affinities, depending on the photoproduct and the transcriptional state of the region. Required for UV-induced CHEK1 phosphorylation and the recruitment of CEP164 to cyclobutane pyrimidine dimmers (CPD), sites of DNA damage after UV irradiation. {ECO:0000269|PubMed:19197159}.;
- Disease
- DISEASE: Xeroderma pigmentosum complementation group A (XP-A) [MIM:278700]: 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. XP-A patients show the most severe skin symptoms and progressive neurological disorders. {ECO:0000269|PubMed:10447254, ECO:0000269|PubMed:1339397, ECO:0000269|PubMed:1372103, ECO:0000269|PubMed:8504220, ECO:0000269|PubMed:9671271}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.553
Intolerance Scores
- LoFtool
- 0.735
- RVIS EVS
- 0.68
- RVIS percentile EVS
- 84.93
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.943
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |