GeneBe

POLH

protein-coding

DNA polymerase eta, the group of DNA polymerases|Xeroderma pigmentosum complementation groups

Gene summary

This gene encodes a member of the Y family of specialized DNA polymerases. It copies undamaged DNA with a lower fidelity than other DNA-directed polymerases. However, it accurately replicates UV-damaged DNA; when thymine dimers are present, this polymerase inserts the complementary nucleotides in the newly synthesized DNA, thereby bypassing the lesion and suppressing the mutagenic effect of UV-induced DNA damage. This polymerase is thought to be involved in hypermutation during immunoglobulin class switch recombination. Mutations in this gene result in XPV, a variant type of xeroderma pigmentosum. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

MANE transcript

NM_006502.3

Inheritance

AR

ClinVar variants

P:64U:139B:178

Top phenotype

Xeroderma pigmentosum, variant type

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr6:43,576,185-43,620,523

External References & Databases

Ensembl (ENSG00000170734)NCBI Gene (5429)OMIM (603968)HGNC:9181GenCCUniProt (Q9Y253)AlphaFoldClinVar (POLH)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~44.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

xeroderma pigmentosum variant typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010214

Submitter: Genomics England PanelApp

xeroderma pigmentosum variant typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010214

Submitter: G2P

xeroderma pigmentosum variant typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010214

Submitter: PanelApp Australia

xeroderma pigmentosum variant typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010214

Submitter: Labcorp Genetics (formerly Invitae)

xeroderma pigmentosum variant typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010214

Submitter: ClinGen

There is abundant evidence published associating the POLH gene with xeroderma pigmentosum variant type since the gene-disease relationship was first proposed by Masutani et al. (1999). Multiple case level studies have been performed with XPV patients that have variants in the POLH 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 Polh deficient mouse models have been established to show consistent phenotypes with XPV patients, including highly susceptible to ultraviolet-induced carcinogenesis and the formation of epithelial and mesenchymal tumors. All of these types of evidence are consistent with a definitive relationship between the POLH gene and xeroderma pigmentosum variant type.

xeroderma pigmentosum variant typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010214

Submitter: Orphanet

Clinical Genomic Database (CGD)

Xeroderma pigmentosum, variant typeAR

Manifestation: Dermatologic; Oncologic

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: 10398605; 10385124; 20301571; 23630442; 23651273; 23755135Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLH variants in ClinVar

8 Conditions Cataloged
not providedTotal: 341
Inborn genetic diseasesTotal: 87
Xeroderma pigmentosum variant typeTotal: 85
Xeroderma pigmentosumTotal: 36
not specifiedTotal: 33
POLH-related disorderTotal: 16
Malignant tumor of breastTotal: 1
See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006502.3. 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
2
clinvar
159
clinvar
 161
missense
4
clinvar
129
clinvar
18
clinvar
1
clinvar
 152
nonsense
18
clinvar
6
clinvar
1
clinvar
 25
start loss
0
frameshift
17
clinvar
11
clinvar
3
clinvar
 31
splice donor/acceptor (+/-2bp)
3
clinvar
5
clinvar
4
clinvar
 12
Total38261391771381

Highest pathogenic variant AF is 0.00017472422

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006502.3RefSeqNP_006493.110MANE Select
ENST00000372236.9EnsemblENSP00000361310.410MANE Select
NM_001291969.2RefSeqNP_001278898.18Standard
NM_001291970.2RefSeqNP_001278899.110Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Fanconi anemia pathway - Homo sapiens (human)
  • HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
  • DNA Repair
  • DNA Double-Strand Break Repair
  • Homology Directed Repair

Biological Process

  • DNA synthesis involved in DNA repair
  • DNA replication
  • DNA repair
  • regulation of DNA repair
  • pyrimidine dimer repair

Molecular Function

  • damaged DNA binding
  • DNA-directed DNA polymerase activity
  • protein binding
  • metal ion binding

Cellular Component

  • nucleus
  • nucleoplasm
  • replication fork
  • cytosol
  • site of double-strand break

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000372236
Coding exons
10
Length
42815
Individuals with no LoFs
125668
Homozygous LoFs
0
Heterozygous LoFs
80
Defined
125748
p
0.000318
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8173403850.8830.00002124638
Missense (PolyPhen)7492.3060.801681089
Synonymous0.1661361380.9820.000007141437
Loss of Function2.301933.30.5700.00000176378

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000680.00068rare
Latino/Admixed American0.000320.00032rare
Ashkenazi Jewish00.0absent
East Asian0.000980.00098rare
Finnish0.0000470.000046rare
European (Non-Finnish)0.000210.00021rare
South Asian0.000460.00046rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: DNA polymerase specifically involved in the DNA repair by translesion synthesis (TLS) (PubMed:10385124, PubMed:11743006, PubMed:24449906). Due to low processivity on both damaged and normal DNA, cooperates with the heterotetrameric (REV3L, REV7, POLD2 and POLD3) POLZ complex for complete bypass of DNA lesions. Inserts one or 2 nucleotide(s) opposite the lesion, the primer is further extended by the tetrameric POLZ complex. In the case of 1,2-intrastrand d(GpG)-cisplatin cross-link, inserts dCTP opposite the 3' guanine (PubMed:24449906). Particularly important for the repair of UV-induced pyrimidine dimers (PubMed:10385124, PubMed:11743006). Although inserts the correct base, may cause base transitions and transversions depending upon the context. May play a role in hypermutation at immunoglobulin genes (PubMed:11376341, PubMed:14734526). Forms a Schiff base with 5'- deoxyribose phosphate at abasic sites, but does not have any lyase activity, preventing the release of the 5'-deoxyribose phosphate (5'-dRP) residue. This covalent trapping of the enzyme by the 5'- dRP residue inhibits its DNA synthetic activity during base excision repair, thereby avoiding high incidence of mutagenesis (PubMed:14630940). Targets POLI to replication foci (PubMed:12606586). {ECO:0000269|PubMed:10385124, ECO:0000269|PubMed:11376341, ECO:0000269|PubMed:11743006, ECO:0000269|PubMed:12606586, ECO:0000269|PubMed:14630940, ECO:0000269|PubMed:14734526, ECO:0000269|PubMed:24449906}.;
Disease
DISEASE: Xeroderma pigmentosum variant type (XPV) [MIM:278750]: 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. XPV shows normal nucleotide excision repair, but an exaggerated delay in recovery of replicative DNA synthesis. Most patients with the variant type of xeroderma pigmentosum do not develop clinical symptoms and skin neoplasias until a later age. Clinical manifestations are limited to photo-induced deterioration of the skin and eyes. {ECO:0000269|PubMed:10385124, ECO:0000269|PubMed:10398605, ECO:0000269|PubMed:11032022, ECO:0000269|PubMed:11121129, ECO:0000269|PubMed:11773631, ECO:0000269|PubMed:24130121}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.163

Intolerance Scores

LoFtool
0.837
RVIS EVS
0.67
RVIS percentile EVS
84.64

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.990

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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