WRN

WRN RecQ like helicase, the group of RecQ like helicases|Exonucleases

Basic information

Region (hg38): 8:31033788-31176138

Links

ENSG00000165392 ∙ NCBI:7486 ∙ OMIM:604611 ∙ HGNC:12791 ∙ Uniprot:Q14191 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• osteosarcoma (Moderate), mode of inheritance: AR
• Werner syndrome (Supportive), mode of inheritance: AR
• Werner syndrome (Definitive), mode of inheritance: AR
• Werner syndrome (Strong), mode of inheritance: AR
• Werner syndrome (Definitive), mode of inheritance: AR
• Werner syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Werner syndrome	AR	Cardiovascular; Endocrine; Obstetric; Oncologic	Individuals typically have insulin resistance, as well as increased risk of atherosclerosis and malignancy (eg, melanomas, osteosarcomas, sarcomas, and thyroid carcinoma) and and awareness may allow preventive measures related to the risk of atherosclerosis, as well as early diagnosis and treatment of atherosclerosis, diabetes mellitus, and malignancy, which may reduce morbidity and mortality; Awareness and interventions related to endocrine complications (eg, metformin treatment for insulin resistance) as well as the potential for obstetric sequelae (eg, cervical incompetence) may be beneficial in the management of reproductive health	Cardiovascular; Craniofacial; Dermatologic; Endocrine; Gastrointestinal; Musculoskeletal; Obstetric; Oncologic; Ophthalmologic	14042963; 7460386; 8722214; 8968742; 8602509; 9048918; 9253306; 9012406; 10220139; 16786514; 17476199; 18205852; 20301687; 20443122; 22654791; 23524889; 23552003; 23849162; 23936869

ClinVar

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

• Werner syndrome (212 variants)
• not provided (6 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the WRN 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	15	601	4	621
missense	2	2	1648	13	4	1669
nonsense	77	31	2	1		111
start loss			1			1
frameshift	125	46	6	1		178
inframe indel		1	41			42
splice donor/acceptor (+/-2bp)	10	87	4	1	2	104
splice region		3	115	144	13	275
non coding		3	39	419	91	552
Total	214	171	1756	1036	101

Highest pathogenic variant AF is 0.0000526

Variants in WRN

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

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

Position	Type	Phenotype	Significance	ClinVar
8-31033810-G-A		Werner syndrome	Uncertain significance (Jan 13, 2018)
8-31033816-T-A		Werner syndrome	Uncertain significance (Jan 12, 2018)
8-31033837-G-A		Werner syndrome	Benign (Jan 13, 2018)
8-31033841-T-G		Werner syndrome	Uncertain significance (Jan 13, 2018)
8-31033853-C-T		Werner syndrome	Uncertain significance (Jan 13, 2018)
8-31033887-C-G		Werner syndrome	Benign (Jan 12, 2018)
8-31033898-G-A		Werner syndrome	Uncertain significance (Jan 12, 2018)
8-31033915-G-C		Werner syndrome	Uncertain significance (Mar 16, 2018)
8-31033929-C-G		Werner syndrome	Uncertain significance (Jan 13, 2018)
8-31058111-G-A			Benign (Jun 28, 2018)
8-31058158-A-C			Benign (Jul 31, 2018)
8-31058411-A-G		Werner syndrome	Uncertain significance (Jan 13, 2018)
8-31058448-A-G		Werner syndrome	Uncertain significance (Jan 26, 2024)
8-31058453-T-G		Werner syndrome	Uncertain significance (Dec 27, 2021)
8-31058454-GA-G		Werner syndrome	Pathogenic/Likely pathogenic (Feb 10, 2024)
8-31058454-G-GA		Werner syndrome	Pathogenic (Apr 19, 2023)
8-31058459-A-G		Werner syndrome	Likely benign (Sep 26, 2023)
8-31058463-T-A		Werner syndrome	Uncertain significance (Mar 09, 2022)
8-31058463-T-C		Werner syndrome	Conflicting classifications of pathogenicity (Jan 28, 2024)
8-31058465-G-A		Werner syndrome	Likely benign (Jan 16, 2023)
8-31058466-GA-G		Werner syndrome	Pathogenic (Oct 01, 2021)
8-31058467-A-T		Werner syndrome	Uncertain significance (Nov 29, 2023)
8-31058468-A-G		Werner syndrome	Likely benign (Jul 30, 2023)
8-31058471-A-C		Werner syndrome	Likely benign (Sep 22, 2023)
8-31058472-A-G		Werner syndrome	Uncertain significance (Oct 12, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
WRN	protein_coding	protein_coding	ENST00000298139	34	139969

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.64e-34	0.0278	125609	0	139	125748	0.000553

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.221	767	750	1.02	0.0000384	9508
Missense in Polyphen		241	254.43	0.94723		3338
Synonymous	-0.0363	263	262	1.00	0.0000142	2549
Loss of Function	1.96	63	82.2	0.767	0.00000426	1007

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00104	0.00104
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.00152	0.00152
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000468	0.000466
Middle Eastern	0.00152	0.00152
South Asian	0.000721	0.000719
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Multifunctional enzyme that has both magnesium and ATP- dependent DNA-helicase activity and 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double- stranded DNA. Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity). Plays a role in double-strand break repair after gamma-irradiation. {ECO:0000250, ECO:0000269|PubMed:11863428, ECO:0000269|PubMed:17563354, ECO:0000269|PubMed:18596042, ECO:0000269|PubMed:19283071, ECO:0000269|PubMed:19652551, ECO:0000269|PubMed:21639834}.
• Disease: DISEASE: Werner syndrome (WRN) [MIM:277700]: A rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus, ocular cataracts and osteoporosis. The major cause of death, at a median age of 47, is myocardial infarction. {ECO:0000269|PubMed:16673358}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Colorectal cancer (CRC) [MIM:114500]: 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:0000305|PubMed:24308539, ECO:0000305|PubMed:9989816}. Note=The disease may be caused by mutations affecting the gene represented in this entry.
• Pathway: HDR through Single Strand Annealing (SSA);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);DNA Repair;Gene expression (Transcription);DNA Double-Strand Break Repair;Generic Transcription Pathway;SUMOylation of DNA damage response and repair proteins;Homology Directed Repair;Post-translational protein modification;SUMO E3 ligases SUMOylate target proteins;Metabolism of proteins;RNA Polymerase II Transcription;G2/M DNA damage checkpoint;G2/M Checkpoints;Cell Cycle Checkpoints;SUMOylation;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Cell Cycle;Regulation of Telomerase;Processing of DNA double-strand break ends;Presynaptic phase of homologous DNA pairing and strand exchange;Homologous DNA Pairing and Strand Exchange;Resolution of D-loop Structures through Holliday Junction Intermediates;Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA);Resolution of D-Loop Structures;HDR through Homologous Recombination (HRR) (Consensus)

Recessive Scores

• pRec: 0.523

Intolerance Scores

• loftool: 0.988
• rvis_EVS: 0.68
• rvis_percentile_EVS: 84.95

Haploinsufficiency Scores

• pHI: 0.912
• hipred: Y
• hipred_score: 0.684
• ghis: 0.503

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0720

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Wrn
• Phenotype: neoplasm; 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); reproductive 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); vision/eye phenotype; digestive/alimentary phenotype; limbs/digits/tail phenotype; skeleton phenotype; immune system phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region 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); craniofacial phenotype

Gene ontology

• Biological process: telomere maintenance;double-strand break repair via homologous recombination;DNA synthesis involved in DNA repair;replicative cell aging;DNA metabolic process;DNA replication;DNA repair;base-excision repair;double-strand break repair;DNA recombination;cellular response to DNA damage stimulus;response to oxidative stress;brain development;aging;cell aging;determination of adult lifespan;cellular response to starvation;response to UV-C;multicellular organism aging;replication fork processing;DNA duplex unwinding;regulation of growth rate;regulation of apoptotic process;G-quadruplex DNA unwinding;positive regulation of hydrolase activity;telomeric D-loop disassembly;cellular response to gamma radiation;nucleic acid phosphodiester bond hydrolysis;t-circle formation;positive regulation of strand invasion;protein localization to nucleolus
• Cellular component: chromosome, telomeric region;nucleus;nucleoplasm;replication fork;DNA replication factor A complex;chromosome;nucleolus;cytoplasm;centrosome;nuclear speck;site of double-strand break;neuron projection
• Molecular function: magnesium ion binding;four-way junction DNA binding;Y-form DNA binding;bubble DNA binding;DNA binding;DNA helicase activity;chromatin binding;ATP-dependent DNA helicase activity;helicase activity;exonuclease activity;protein binding;ATP binding;3'-5' exonuclease activity;four-way junction helicase activity;ATPase activity;manganese ion binding;MutLalpha complex binding;protein homodimerization activity;3'-5' DNA helicase activity;ATP-dependent 3'-5' DNA helicase activity;protein-containing complex binding;G-quadruplex DNA binding;forked DNA-dependent helicase activity;telomeric D-loop binding;telomeric G-quadruplex DNA binding;3'-flap-structured DNA binding;8-hydroxy-2'-deoxyguanosine DNA binding