POLD1

DNA polymerase delta 1, catalytic subunit, the group of DNA polymerases

Basic information

Region (hg38): 19:50384204-50418018

Previous symbols: [ "POLD" ]

Links

ENSG00000062822 ∙ NCBI:5424 ∙ OMIM:174761 ∙ HGNC:9175 ∙ Uniprot:P28340 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mandibular hypoplasia-deafness-progeroid syndrome (Strong), mode of inheritance: AD
• colorectal cancer, susceptibility to, 10 (Strong), mode of inheritance: AD
• mandibular hypoplasia-deafness-progeroid syndrome (Strong), mode of inheritance: AD
• mandibular hypoplasia-deafness-progeroid syndrome (Moderate), mode of inheritance: AD
• colorectal cancer, susceptibility to, 10 (Moderate), mode of inheritance: AD
• mandibular hypoplasia-deafness-progeroid syndrome (Limited), mode of inheritance: AR
• mandibular hypoplasia-deafness-progeroid syndrome (Supportive), mode of inheritance: AD
• Polymerase proofreading-related adenomatous polyposis (Supportive), mode of inheritance: AD
• mandibular hypoplasia-deafness-progeroid syndrome (Strong), mode of inheritance: AD
• colorectal cancer, susceptibility to, 10 (Strong), mode of inheritance: AD
• non-severe combined immunodeficiency due to polymerase delta deficiency (Limited), mode of inheritance: AR
• POLD1-related polyposis and colorectal cancer syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Colorectal cancer, susceptibility to, 10	AD	Allergy/Immunology/Infectious; Oncologic	Described individuals manifest with colorectal adenomas, with a high risk of colorectal carcinoma, and screening (eg, with colonoscopy) may allow early detection and treatment, potentially ameliorating morbidity and mortality; Other neoplasms (eg, an increased risk of endometrial cancer has been reported) have been described in affected individuals, and knowledge of the increased risk may allow early detection and treatment	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Craniofacial; Dermatologic; Endocrine; Musculoskeletal; Oncologic	20631028; 23263490; 23770608; 24501277
Individuals have been described such that the presence of variants would warrant surveillance in the pediatric period

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the POLD1 gene.

• Mandibular hypoplasia-deafness-progeroid syndrome (2 variants)
• POLD1-related disorder (1 variants)
• Hereditary cancer-predisposing syndrome (1 variants)
• not provided (1 variants)
• Colorectal cancer, susceptibility to, 10 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the POLD1 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			21	1114	15	1150
missense	1	2	2000	30	3	2036
nonsense			63			63
start loss			5			5
frameshift			167			167
inframe indel	1		63			64
splice donor/acceptor (+/-2bp)			88	1		89
splice region			141	194	1	336
non coding			41	643	61	745
Total	2	2	2448	1788	79

Variants in POLD1

This is a list of pathogenic ClinVar variants found in the POLD1 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-50384211-C-G			Likely benign (Jul 02, 2018)
19-50384216-G-A			Benign (Jun 21, 2018)
19-50384344-G-A		not specified • Colorectal cancer, susceptibility to, 10	Benign/Likely benign (Dec 01, 2022)
19-50384344-G-C		not specified	Likely benign (Feb 24, 2017)
19-50384348-TCACGGCGG-ACACGGCGA			Uncertain significance (Jan 25, 2017)
19-50384360-A-G		not specified	Likely benign (Oct 11, 2016)
19-50384361-G-A		not specified	Likely benign (Mar 07, 2016)
19-50384369-C-T		not specified	Uncertain significance (Mar 07, 2017)
19-50384387-G-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Jun 15, 2018)
19-50384391-G-C			Uncertain significance (Apr 17, 2018)
19-50384399-A-AG		not specified	Likely benign (Apr 12, 2017)
19-50384402-G-A		not specified	Likely benign (Jun 26, 2017)
19-50384406-A-G		not specified	Likely benign (Jun 02, 2017)
19-50384409-G-A		not specified	Likely benign (Aug 08, 2017)
19-50384437-G-C			Benign (Jun 18, 2018)
19-50384466-A-G			Likely benign (Jun 23, 2018)
19-50398570-C-CA			Benign (Dec 25, 2019)
19-50398570-C-CAA			Benign (Jul 11, 2021)
19-50398595-A-G			Likely benign (Feb 07, 2019)
19-50398636-G-A			Benign (Jan 10, 2019)
19-50398807-T-C		not specified	Benign (Aug 15, 2023)
19-50398822-C-A		not specified	Likely benign (Aug 15, 2023)
19-50398824-TCCACCAAGCTCCAACTTGCCCAGCAGGATGGATGGCAAGCGG-T		Colorectal cancer, susceptibility to, 10	Uncertain significance (Apr 07, 2023)
19-50398839-C-G			Uncertain significance (Apr 26, 2023)
19-50398839-C-T		Carcinoma of colon	Uncertain significance (-)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
POLD1	protein_coding	protein_coding	ENST00000440232	26	33813

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000242	1.00	125687	0	61	125748	0.000243

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.46	561	751	0.747	0.0000539	7013
Missense in Polyphen		210	360.4	0.58268		3360
Synonymous	-0.329	340	332	1.02	0.0000253	2285
Loss of Function	4.39	20	55.2	0.363	0.00000264	608

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000213	0.000210
Ashkenazi Jewish	0.00156	0.00149
East Asian	0.00	0.00
Finnish	0.000143	0.000139
European (Non-Finnish)	0.000265	0.000255
Middle Eastern	0.00	0.00
South Asian	0.000233	0.000229
Other	0.000332	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: As the catalytic component of the trimeric (Pol-delta3 complex) and tetrameric DNA polymerase delta complexes (Pol-delta4 complex), plays a crucial role in high fidelity genome replication, including in lagging strand synthesis, and repair. Exhibits both DNA polymerase and 3'- to 5'-exonuclease activities (PubMed:16510448, PubMed:19074196, PubMed:20334433, PubMed:24035200, PubMed:24022480). Requires the presence of accessory proteins POLD2, POLD3 and POLD4 for full activity. Depending upon the absence (Pol-delta3) or the presence of POLD4 (Pol-delta4), displays differences in catalytic activity. Most notably, expresses higher proofreading activity in the context of Pol-delta3 compared with that of Pol-delta4 (PubMed:19074196, PubMed:20334433). Although both Pol-delta3 and Pol-delta4 process Okazaki fragments in vitro, Pol-delta3 may be better suited to fulfill this task, exhibiting near-absence of strand displacement activity compared to Pol-delta4 and stalling on encounter with the 5'-blocking oligonucleotides. Pol-delta3 idling process may avoid the formation of a gap, while maintaining a nick that can be readily ligated (PubMed:24035200). Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation (PubMed:20227374). Under conditions of DNA replication stress, in the presence of POLD3 and POLD4, may catalyze the repair of broken replication forks through break-induced replication (BIR) (PubMed:24310611). Involved in the translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites (PubMed:19074196). {ECO:0000269|PubMed:16510448, ECO:0000269|PubMed:19074196, ECO:0000269|PubMed:20227374, ECO:0000269|PubMed:20334433, ECO:0000269|PubMed:24022480, ECO:0000269|PubMed:24035200, ECO:0000269|PubMed:24310611}.
• Disease: DISEASE: Colorectal cancer 10 (CRCS10) [MIM:612591]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:23263490, ECO:0000269|PubMed:24501277}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) [MIM:615381]: An autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, metabolic abnormalities including insulin resistance and diabetes mellitus, sclerodermatous skin, and a facial appearance characterized by mandibular hypoplasia. Sensorineural deafness occurs late in the first or second decades of life. {ECO:0000269|PubMed:23770608}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Nucleotide excision repair - Homo sapiens (human);Pyrimidine metabolism - Homo sapiens (human);Base excision repair - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Mismatch repair - Homo sapiens (human);DNA replication - Homo sapiens (human);Purine metabolism - Homo sapiens (human);Homologous recombination - Homo sapiens (human);Homologous recombination;Pyrimidine metabolism;Nucleotide Metabolism;DNA Replication;Mismatch repair;Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta);Mismatch Repair;HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);DNA Repair;DNA Double-Strand Break Repair;Homology Directed Repair;Polymerase switching on the C-strand of the telomere;Purine metabolism;DNA Replication;Pyrimidine metabolism;Polymerase switching;Leading Strand Synthesis;Removal of the Flap Intermediate;Processive synthesis on the lagging strand;Lagging Strand Synthesis;DNA strand elongation;Synthesis of DNA;S Phase;PCNA-Dependent Long Patch Base Excision Repair;Resolution of AP sites via the multiple-nucleotide patch replacement pathway;Resolution of Abasic Sites (AP sites);Base Excision Repair;Removal of the Flap Intermediate from the C-strand;Processive synthesis on the C-strand of the telomere;Telomere C-strand (Lagging Strand) Synthesis;Extension of Telomeres;Telomere Maintenance;Chromosome Maintenance;Recognition of DNA damage by PCNA-containing replication complex;Termination of translesion DNA synthesis;Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template;DNA Damage Bypass;Cell Cycle;Dual Incision in GG-NER;Gap-filling DNA repair synthesis and ligation in GG-NER;Global Genome Nucleotide Excision Repair (GG-NER);Cell Cycle, Mitotic;Dual incision in TC-NER;Gap-filling DNA repair synthesis and ligation in TC-NER;Transcription-Coupled Nucleotide Excision Repair (TC-NER);Nucleotide Excision Repair;Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha);HDR through Homologous Recombination (HRR) (Consensus)

Recessive Scores

• pRec: 0.456

Intolerance Scores

• loftool: 0.656
• rvis_EVS: -0.83
• rvis_percentile_EVS: 11.54

Haploinsufficiency Scores

• pHI: 0.964
• hipred: Y
• hipred_score: 0.520
• ghis: 0.642

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.923

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pold1
• Phenotype: muscle phenotype; cellular phenotype; endocrine/exocrine gland phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); 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); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); immune system phenotype; embryo phenotype; neoplasm

Zebrafish Information Network

• Gene name: pold1
• Affected structure: pharyngeal arch 3-7
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• Biological process: telomere maintenance;DNA synthesis involved in DNA repair;DNA replication;DNA-dependent DNA replication;DNA repair;transcription-coupled nucleotide-excision repair;base-excision repair, gap-filling;nucleotide-excision repair, DNA incision, 5'-to lesion;nucleotide-excision repair, DNA gap filling;response to UV;translesion synthesis;telomere maintenance via semi-conservative replication;nucleotide-excision repair, DNA incision;cellular response to UV;DNA damage response, detection of DNA damage;DNA replication proofreading;fatty acid homeostasis
• Cellular component: nucleotide-excision repair complex;nuclear chromosome, telomeric region;nucleus;nucleoplasm;cytosol;membrane;aggresome;delta DNA polymerase complex
• Molecular function: nucleotide binding;DNA binding;chromatin binding;damaged DNA binding;DNA-directed DNA polymerase activity;protein binding;3'-5'-exodeoxyribonuclease activity;metal ion binding;4 iron, 4 sulfur cluster binding