POLA1

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

Basic information

Region (hg38): X:24693872-24996986

Previous symbols: [ "POLA", "NSX" ]

Links

ENSG00000101868 ∙ NCBI:5422 ∙ OMIM:312040 ∙ HGNC:9173 ∙ Uniprot:P09884 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• X-linked intellectual disability, van Esch type (Definitive), mode of inheritance: XLR
• X-linked reticulate pigmentary disorder (Moderate), mode of inheritance: XL
• X-linked intellectual disability, van Esch type (Moderate), mode of inheritance: XL
• X-linked reticulate pigmentary disorder (Supportive), mode of inheritance: XL
• X-linked intellectual disability, van Esch type (Supportive), mode of inheritance: XL
• X-linked intellectual disability, van Esch type (Definitive), mode of inheritance: XL
• X-linked reticulate pigmentary disorder (Strong), mode of inheritance: XL
• X-linked intellectual disability, van Esch type (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pigmentary disorder, reticulate, with systemic manifestations, X-linked; Van Esch-O'Driscoll syndrome	XL	Allergy/Immunology/Infectious	Males have been described with manifestations including recurrent respiratory infections and failure to thrive due to inflammatory gastroenteritis or colitis, and awareness, and awareness may allow preventative measures and early and aggressive treatments of infections	Allergy/Immunology/Infectious; Craniofacial; Dermatologic; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic	16053905; 27019227; 31006512

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the POLA1 gene.

• not provided (444 variants)
• Inborn genetic diseases (30 variants)
• X-linked intellectual disability, van Esch type (12 variants)
• not specified (10 variants)
• POLA1-related condition (6 variants)
• X-linked reticulate pigmentary disorder (6 variants)
• X-linked reticulate pigmentary disorder;X-linked intellectual disability, van Esch type (3 variants)
• X-linked intellectual disability, van Esch type;X-linked reticulate pigmentary disorder (2 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the POLA1 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			1	98	12	111
missense		1	215	17	19	252
nonsense						0
start loss						0
frameshift			1			1
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1		2			3
splice region			7	15	8	30
non coding	1		5	52	16	74
Total	2	1	225	167	47

Highest pathogenic variant AF is 0.00000896

Variants in POLA1

This is a list of pathogenic ClinVar variants found in the POLA1 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-24693900-G-A			Uncertain significance (Sep 29, 2021)
X-24693969-C-T			Uncertain significance (Nov 18, 2023)
X-24693974-C-T			Uncertain significance (Nov 13, 2023)
X-24693977-G-A			Uncertain significance (Oct 18, 2023)
X-24693978-G-A			Uncertain significance (May 03, 2022)
X-24693982-C-T			Likely benign (Dec 13, 2023)
X-24694000-G-A			Likely benign (Jun 04, 2023)
X-24699423-A-G			Uncertain significance (Dec 06, 2022)
X-24699424-G-T			Uncertain significance (Mar 17, 2023)
X-24699428-T-C			Uncertain significance (Jun 06, 2023)
X-24699436-T-C		POLA1-related disorder	Uncertain significance (Jun 07, 2023)
X-24699449-T-C			Uncertain significance (Oct 05, 2023)
X-24699458-G-A			Uncertain significance (Jun 11, 2022)
X-24699463-C-T			Uncertain significance (Dec 13, 2022)
X-24699464-G-A		Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 04, 2024)
X-24699473-A-G			Uncertain significance (Jun 01, 2022)
X-24699475-A-AATG			Uncertain significance (May 11, 2023)
X-24699477-A-G			Likely benign (May 16, 2023)
X-24699482-A-G			Uncertain significance (Apr 20, 2022)
X-24699490-C-A		Inborn genetic diseases	Likely benign (Jan 08, 2024)
X-24699490-C-T			Uncertain significance (Aug 17, 2022)
X-24699491-G-A		Inborn genetic diseases	Uncertain significance (Mar 10, 2022)
X-24699495-A-G			Likely benign (Jan 11, 2024)
X-24699513-G-A			Likely benign (Sep 23, 2022)
X-24699526-G-A			Uncertain significance (Jul 04, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
POLA1	protein_coding	protein_coding	ENST00000379059	37	303068

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	7.70e-10	107638	0	1	107639	0.00000465

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.99	384	511	0.752	0.0000384	9673
Missense in Polyphen		90	169	0.53255		3064
Synonymous	-0.911	201	185	1.09	0.0000142	2645
Loss of Function	7.04	0	57.7	0.00	0.00000452	1044

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000473	0.0000473
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays an essential role in the initiation of DNA replication. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes. In the cytosol, responsible for a substantial proportion of the physiological concentration of cytosolic RNA:DNA hybrids, which are necessary to prevent spontaneous activation of type I interferon responses (PubMed:27019227). {ECO:0000269|PubMed:27019227, ECO:0000269|PubMed:9518481}.
• Disease: DISEASE: Pigmentary disorder, reticulate, with systemic manifestations, X-linked (PDR) [MIM:301220]: A X-linked recessive disorder characterized by recurrent infections and sterile inflammation in various organs. Diffuse skin hyperpigmentation with a distinctive reticulate pattern is universally evident by early childhood. This is later followed in many patients by hypohidrosis, corneal inflammation and scarring, enterocolitis that resembles inflammatory bowel disease, and recurrent urethral strictures. Melanin and amyloid deposition is present in the dermis. Affected males also have a characteristic facies with frontally upswept hair and flared eyebrows. Female carriers have only restricted pigmentary changes along Blaschko's lines. {ECO:0000269|PubMed:27019227}. Note=The disease is caused by mutations affecting the gene represented in this entry. XLPDR is caused by a recurrent intronic mutation that results in missplicing and reduced POLA1 expression. This leads to a decrease in cytosolic RNA:DNA hybrids and constitutive activation of type I interferon responses, but has no effect on cell replication. {ECO:0000269|PubMed:27019227}.
• Pathway: Pyrimidine metabolism - Homo sapiens (human);DNA replication - Homo sapiens (human);Purine metabolism - Homo sapiens (human);Mitotic G1-G1-S phases;Retinoblastoma (RB) in Cancer;Pyrimidine metabolism;Nucleotide Metabolism;DNA Replication;Inhibition of replication initiation of damaged DNA by RB1/E2F1;Polymerase switching on the C-strand of the telomere;Purine metabolism;Activation of E2F1 target genes at G1/S;G1/S-Specific Transcription;Activation of the pre-replicative complex;E2F mediated regulation of DNA replication;Mitotic G1-G1/S phases;DNA replication initiation;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;Telomere C-strand synthesis initiation;Telomere C-strand (Lagging Strand) Synthesis;Extension of Telomeres;Telomere Maintenance;Chromosome Maintenance;G1/S Transition;DNA Replication Pre-Initiation;M/G1 Transition;Cell Cycle;Cell Cycle, Mitotic;E2F transcription factor network (Consensus)

Recessive Scores

• pRec: 0.303

Intolerance Scores

• loftool: 0.0993
• rvis_EVS: -0.8
• rvis_percentile_EVS: 12.53

Haploinsufficiency Scores

• pHI: 0.996
• hipred: Y
• hipred_score: 0.796
• ghis: 0.639

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.654

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pola1
• Phenotype: normal phenotype

Zebrafish Information Network

• Gene name: pola1
• Affected structure: trunk
• Phenotype tag: abnormal
• Phenotype quality: necrotic

Gene ontology

• Biological process: G1/S transition of mitotic cell cycle;regulation of transcription involved in G1/S transition of mitotic cell cycle;DNA synthesis involved in DNA repair;DNA replication;DNA replication, synthesis of RNA primer;DNA replication initiation;DNA strand elongation involved in DNA replication;leading strand elongation;lagging strand elongation;DNA repair;nucleotide-excision repair;double-strand break repair via nonhomologous end joining;cell population proliferation;viral process;telomere maintenance via semi-conservative replication;mitotic DNA replication initiation;synthesis of RNA primer involved in mitotic DNA replication;DNA synthesis involved in UV-damage excision repair
• Cellular component: chromatin;nucleus;nuclear envelope;nucleoplasm;alpha DNA polymerase:primase complex;nucleolus;cytosol;nuclear matrix
• Molecular function: nucleotide binding;nucleoside binding;DNA binding;chromatin binding;DNA replication origin binding;DNA-directed DNA polymerase activity;protein binding;purine nucleotide binding;protein kinase binding;metal ion binding;protein heterodimerization activity;4 iron, 4 sulfur cluster binding