POLH

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

Basic information

Region (hg38): 6:43576184-43620523

Links

ENSG00000170734 ∙ NCBI:5429 ∙ OMIM:603968 ∙ HGNC:9181 ∙ Uniprot:Q9Y253 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• xeroderma pigmentosum variant type (Supportive), mode of inheritance: AR
• xeroderma pigmentosum variant type (Definitive), mode of inheritance: AR
• xeroderma pigmentosum variant type (Definitive), mode of inheritance: AR
• xeroderma pigmentosum variant type (Strong), mode of inheritance: AR
• xeroderma pigmentosum variant type (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Xeroderma pigmentosum, variant type	AR	Dermatologic; Oncologic	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	Dermatologic; Oncologic	10398605; 10385124; 20301571; 23630442; 23651273; 23755135

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the POLH gene.

• Xeroderma pigmentosum variant type (221 variants)
• not provided (147 variants)
• Xeroderma pigmentosum (54 variants)
• Inborn genetic diseases (22 variants)
• not specified (12 variants)
• Malignant tumor of breast (1 variants)
• POLH-related condition (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the POLH gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	39	1	43
missense		1	54	7	2	64
nonsense	13	3				16
start loss						0
frameshift	7	2	1			10
inframe indel			1			1
splice donor/acceptor (+/-2bp)	2	1				3
splice region			8	5	1	14
non coding			124	37	54	215
Total	22	7	183	83	57

Highest pathogenic variant AF is 0.0000329

Variants in POLH

This is a list of pathogenic ClinVar variants found in the POLH region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-43576193-G-C		Xeroderma pigmentosum variant type	Uncertain significance (Jan 12, 2018)
6-43576203-C-G		Xeroderma pigmentosum variant type	Uncertain significance (Jan 12, 2018)
6-43576206-G-T		Xeroderma pigmentosum variant type	Uncertain significance (Jan 13, 2018)
6-43576213-C-A		Xeroderma pigmentosum variant type	Uncertain significance (Jan 13, 2018)
6-43576226-T-A		Xeroderma pigmentosum variant type	Uncertain significance (Jan 12, 2018)
6-43576229-C-T		Xeroderma pigmentosum variant type	Uncertain significance (Jan 12, 2018)
6-43576250-G-A		Xeroderma pigmentosum variant type	Uncertain significance (Jan 12, 2018)
6-43576328-C-T		Xeroderma pigmentosum variant type	Benign (Jan 13, 2018)
6-43576347-A-C		Xeroderma pigmentosum variant type	Benign (Jan 13, 2018)
6-43576351-A-G		Xeroderma pigmentosum variant type	Uncertain significance (Jan 13, 2018)
6-43576355-GC-G		Xeroderma pigmentosum	Uncertain significance (Jun 14, 2016)
6-43576383-C-T		Xeroderma pigmentosum variant type	Uncertain significance (Jan 13, 2018)
6-43576443-A-G		Xeroderma pigmentosum variant type • Xeroderma pigmentosum	Uncertain significance (Dec 13, 2021)
6-43582313-C-T			Uncertain significance (Sep 21, 2020)
6-43582315-G-C		Xeroderma pigmentosum variant type	Conflicting classifications of pathogenicity (May 19, 2023)
6-43582326-A-G		Xeroderma pigmentosum variant type	Uncertain significance (Jan 13, 2018)
6-43582328-T-G			Likely benign (Jan 14, 2023)
6-43582343-G-A			Likely benign (Nov 20, 2023)
6-43582343-G-T			Likely benign (Dec 16, 2022)
6-43582344-G-T		Xeroderma pigmentosum variant type	Uncertain significance (Jan 13, 2018)
6-43582352-C-T			Likely benign (Dec 14, 2023)
6-43582353-G-C		Xeroderma pigmentosum variant type	Uncertain significance (Jan 12, 2018)
6-43582366-GT-G			Pathogenic (May 28, 2023)
6-43582370-TTTTG-T		Xeroderma pigmentosum variant type	Pathogenic (Jun 17, 1999)
6-43582407-A-C			Likely benign (Sep 09, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
POLH	protein_coding	protein_coding	ENST00000372236	10	42815

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.54e-9	0.984	125668	0	80	125748	0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.817	340	385	0.883	0.0000212	4638
Missense in Polyphen		74	92.306	0.80168		1089
Synonymous	0.166	136	138	0.982	0.00000714	1437
Loss of Function	2.30	19	33.3	0.570	0.00000176	378

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000997	0.000995
Ashkenazi Jewish	0.00	0.00
East Asian	0.000979	0.000979
Finnish	0.0000471	0.0000462
European (Non-Finnish)	0.000211	0.000211
Middle Eastern	0.000979	0.000979
South Asian	0.000461	0.000457
Other	0.000163	0.000163

dbNSFP

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.
• Pathway: 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;Purine metabolism;Pyrimidine metabolism;Translesion Synthesis by POLH;Termination of translesion DNA synthesis;Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template;DNA Damage Bypass;HDR through Homologous Recombination (HRR) (Consensus)

Recessive Scores

• pRec: 0.163

Intolerance Scores

• loftool: 0.837
• rvis_EVS: 0.67
• rvis_percentile_EVS: 84.64

Haploinsufficiency Scores

• pHI: 0.106
• hipred: Y
• hipred_score: 0.592
• ghis: 0.530

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.990

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Polh
• Phenotype: craniofacial phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; immune system phenotype; hearing/vestibular/ear phenotype; neoplasm; pigmentation phenotype; hematopoietic system phenotype

Gene ontology

• Biological process: DNA synthesis involved in DNA repair;DNA replication;DNA repair;regulation of DNA repair;pyrimidine dimer repair;response to radiation;response to UV-C;translesion synthesis;error-prone translesion synthesis;error-free translesion synthesis;cellular response to UV-C
• Cellular component: nucleus;nucleoplasm;replication fork;cytosol;site of double-strand break
• Molecular function: damaged DNA binding;DNA-directed DNA polymerase activity;protein binding;metal ion binding