RPA1

replication protein A1, the group of Nucleotide excision repair

Basic information

Region (hg38): 17:1829701-1900082

Links

ENSG00000132383 ∙ NCBI:6117 ∙ OMIM:179835 ∙ HGNC:10289 ∙ Uniprot:P27694 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• pulmonary fibrosis and/or bone marrow failure, telomere-related, 6 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6	AD	Allergy/Immunology/Infectious; Hematologic; Pulmonary	The condition can involve immunologic manifestations, and awareness may allow early diagnosis and medical management (eg, with IVIG); Surveillance and prompt treatment of bone marrow failure may reduce morbidity; For treatment related to pulmonary fibrosis, early recognition may allow prompt medical management; HSCT has been described	Allergy/Immunology/Infectious; Dermatologic; Hematologic; Pulmonary	34767620

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RPA1 gene.

• Inborn genetic diseases (23 variants)
• not specified (7 variants)
• not provided (2 variants)
• Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6 (1 variants)
• RPA1-related short telomere syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RPA1 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					4	4
missense			23	1		24
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region					1	1
non coding					4	4
Total	0	0	23	1	8

Variants in RPA1

This is a list of pathogenic ClinVar variants found in the RPA1 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-1830105-A-G		not specified	Benign (Jan 24, 2024)
17-1842798-C-A			Benign (Jun 05, 2018)
17-1842819-G-C		not specified	Uncertain significance (Dec 08, 2023)
17-1843952-G-A			Benign (Jun 05, 2018)
17-1843990-C-G		not specified	Uncertain significance (Aug 04, 2021)
17-1844585-G-A		not specified	Uncertain significance (Sep 22, 2023)
17-1844682-G-A		not specified	Uncertain significance (Dec 07, 2021)
17-1844734-A-G		not specified	Benign (Jan 24, 2024)
17-1853057-A-G		not specified	Benign (Jan 24, 2024)
17-1853102-A-G		not specified	Uncertain significance (Feb 03, 2022)
17-1853142-C-G		not specified	Uncertain significance (Mar 11, 2022)
17-1853164-T-G		not specified	Uncertain significance (Nov 15, 2021)
17-1872510-T-G		not specified	Uncertain significance (Jan 26, 2023)
17-1875675-A-G		not specified	Uncertain significance (Oct 06, 2021)
17-1875678-G-A		not specified	Uncertain significance (Nov 21, 2022)
17-1875679-C-T		not specified	Uncertain significance (Nov 21, 2022)
17-1877286-T-A		not specified	Uncertain significance (Oct 12, 2021)
17-1877304-T-C		Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6	Pathogenic (May 10, 2023)
17-1879020-G-A		Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6	Pathogenic (May 10, 2023)
17-1879033-A-G		not specified	Uncertain significance (Dec 28, 2023)
17-1879263-A-G		RPA1-related short telomere syndrome • Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6	Uncertain significance (Sep 10, 2018)
17-1879296-A-G		not specified	Uncertain significance (Apr 05, 2023)
17-1879297-A-G		not specified	Uncertain significance (Aug 08, 2022)
17-1879326-G-A		not specified	Uncertain significance (Jan 23, 2024)
17-1879330-A-G		not specified	Likely benign (Oct 04, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RPA1	protein_coding	protein_coding	ENST00000254719	17	70381

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0878	0.912	125724	0	23	125747	0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.22	292	357	0.819	0.0000205	4043
Missense in Polyphen		83	118.6	0.69984		1339
Synonymous	-0.117	141	139	1.01	0.00000908	1149
Loss of Function	4.34	10	39.4	0.254	0.00000235	415

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000177	0.000177
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000545	0.0000544
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.000115	0.000114
Middle Eastern	0.0000545	0.0000544
South Asian	0.0000986	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates, that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism (PubMed:27723720, PubMed:27723717). Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage (PubMed:9430682). In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response (PubMed:24332808). It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin in response to DNA damage (PubMed:17765923). Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair (PubMed:7697716). Plays also a role in base excision repair (BER) probably through interaction with UNG (PubMed:9765279). Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. May also play a role in telomere maintenance (PubMed:17959650). As part of the alternative replication protein A complex, aRPA, binds single- stranded DNA and probably plays a role in DNA repair. Compared to the RPA2-containing, canonical RPA complex, may not support chromosomal DNA replication and cell cycle progression through S- phase. The aRPA may not promote efficient priming by DNA polymerase alpha but could support DNA synthesis by polymerase delta in presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange (PubMed:19996105). {ECO:0000269|PubMed:12791985, ECO:0000269|PubMed:17765923, ECO:0000269|PubMed:17959650, ECO:0000269|PubMed:19116208, ECO:0000269|PubMed:19996105, ECO:0000269|PubMed:24332808, ECO:0000269|PubMed:27723717, ECO:0000269|PubMed:27723720, ECO:0000269|PubMed:7697716, ECO:0000269|PubMed:7700386, ECO:0000269|PubMed:9430682, ECO:0000269|PubMed:9765279}.
• Pathway: Fanconi anemia pathway - Homo sapiens (human);Nucleotide excision repair - Homo sapiens (human);Mismatch repair - Homo sapiens (human);DNA replication - Homo sapiens (human);Homologous recombination - Homo sapiens (human);Homologous recombination;Retinoblastoma (RB) in Cancer;ATR Signaling;G1 to S cell cycle control;DNA Replication;Mismatch repair;Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta);Mismatch Repair;HDR through Single Strand Annealing (SSA);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);Fanconi Anemia Pathway;DNA Repair;Gene expression (Transcription);DNA Double-Strand Break Repair;HSF1 activation;hypoxia and p53 in the cardiovascular system;Generic Transcription Pathway;Regulation of HSF1-mediated heat shock response;SUMOylation of DNA damage response and repair proteins;Homology Directed Repair;Cellular responses to stress;Post-translational protein modification;SUMO E3 ligases SUMOylate target proteins;Metabolism of proteins;RNA Polymerase II Transcription;G2/M DNA damage checkpoint;Activation of ATR in response to replication stress;G2/M Checkpoints;Cell Cycle Checkpoints;Activation of the pre-replicative complex;Mitotic G1-G1/S phases;DNA Replication;Removal of the Flap Intermediate;Processive synthesis on the lagging strand;Lagging Strand Synthesis;DNA strand elongation;Synthesis of DNA;SUMOylation;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;Cellular responses to external stimuli;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;atm signaling pathway;Fanconi anemia pathway;Cellular response to heat stress;G1/S Transition;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Recognition of DNA damage by PCNA-containing replication complex;Translesion synthesis by REV1;Translesion Synthesis by POLH;Translesion synthesis by POLK;DNA Replication Pre-Initiation;M/G1 Transition;Translesion synthesis by POLI;Termination of translesion DNA synthesis;Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template;DNA Damage Bypass;Cell Cycle;Formation of Incision Complex in GG-NER;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;Processing of DNA double-strand break ends;ATR signaling pathway;Dual incision in TC-NER;Presynaptic phase of homologous DNA pairing and strand exchange;Homologous DNA Pairing and Strand Exchange;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: 0.160

Intolerance Scores

• loftool: 0.638
• rvis_EVS: -1.11
• rvis_percentile_EVS: 6.78

Haploinsufficiency Scores

• pHI: 0.998
• hipred: Y
• hipred_score: 0.793
• ghis: 0.686

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.985

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rpa1
• Phenotype: cellular phenotype; immune 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); hematopoietic system phenotype; 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); neoplasm

Zebrafish Information Network

• Gene name: rpa1
• Affected structure: head
• Phenotype tag: abnormal
• Phenotype quality: flat

Gene ontology

• Biological process: G1/S transition of mitotic cell cycle;telomere maintenance;double-strand break repair via homologous recombination;DNA replication;DNA-dependent DNA replication;DNA unwinding involved in DNA replication;DNA repair;transcription-coupled nucleotide-excision repair;base-excision repair;nucleotide-excision repair;nucleotide-excision repair, preincision complex stabilization;nucleotide-excision repair, preincision complex assembly;nucleotide-excision repair, DNA incision, 5'-to lesion;nucleotide-excision repair, DNA gap filling;mismatch repair;DNA recombination;cellular response to DNA damage stimulus;telomere maintenance via telomerase;translesion synthesis;telomere maintenance via semi-conservative replication;nucleotide-excision repair, DNA incision;protein localization to chromosome;interstrand cross-link repair;error-prone translesion synthesis;DNA damage response, detection of DNA damage;meiotic cell cycle;error-free translesion synthesis;regulation of cellular response to heat
• Cellular component: nuclear chromosome, telomeric region;nucleus;nucleoplasm;DNA replication factor A complex;PML body;site of DNA damage
• Molecular function: damaged DNA binding;single-stranded DNA binding;protein binding;single-stranded telomeric DNA binding;sequence-specific DNA binding;metal ion binding;G-rich strand telomeric DNA binding