WRN

protein-coding

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

Gene summary

This gene encodes a member of the RecQ subfamily of DNA helicase proteins. The encoded nuclear protein is important in the maintenance of genome stability and plays a role in DNA repair, replication, transcription and telomere maintenance. This protein contains a N-terminal 3' to 5' exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal. Defects in this gene are the cause of Werner syndrome, an autosomal recessive disorder characterized by accelerated aging and an elevated risk for certain cancers. [provided by RefSeq, Aug 2017]

MANE transcript

NM_000553.6

Inheritance

ClinVar variants

P:436U:1778B:743

Top phenotype

Werner syndrome

gnomAD constraint

pLI —, LoF o/e 0.77

Max pathogenic AF

—

Genomic locus

chr8:31,033,788-31,176,138

External References & Databases

Ensembl (ENSG00000165392)

Transcript & Mutation Effects

hg38 • Region Span ~142.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Werner syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010196

Submitter: Orphanet

Werner syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010196

Submitter: PanelApp Australia

Werner syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010196

Submitter: Ambry Genetics

Werner syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010196

Submitter: G2P

Werner syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010196

Submitter: Labcorp Genetics (formerly Invitae)

osteosarcomaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009807

Submitter: Genomics England PanelApp

Werner syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010196

Submitter: ClinGen

There is abundant evidence published associating the WRN gene with Werner Syndrome since the gene-disease relationship was first proposed by Yu et al. (1996). Multiple case level studies have been performed with WS patients that have variants in the WRN gene. There are currently 85 different mutations recorded in Werner Syndrome Mutational Database. BLM and RECQL4, another two RecQ DNA helicases, are associated with Bloom and Rothmund–Thomson syndromes. All three are disorders of chromosomal instability and manifest growth retardation, and predisposition to malignancies. Fibroblasts from individuals with Werner Syndrome have accelerated telomere attrition and undergo premature senescence that can be rescued by enforced expression of Tert. Multiple WRN deficient mouse models have been established to show consistent phenotypes with WS patients, including premature death, hair graying, alopecia, osteoporosis, type II diabetes and cataracts. All of these types of evidence are consistent with a definitive relationship between the WRN gene and Werner Syndrome (WS).

Clinical Genomic Database (CGD)

Werner syndromeAR

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Endocrine; Gastrointestinal; Musculoskeletal; Obstetric; Oncologic; Ophthalmologic

Intervention: Cardiovascular; Endocrine; Obstetric; Oncologic

Rationale: 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

Refs: 14042963; 7460386; 8722214; 8968742; 8602509; 9048918; 9253306; 9012406; 10220139; 16786514; 17476199; 18205852; 20301687; 20443122; 22654791; 23524889; 23552003; 23849162; 23936869

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WRN variants in ClinVar

17 Conditions Cataloged

Werner syndromeTotal: 3632

not providedTotal: 230

Inborn genetic diseasesTotal: 149

not specifiedTotal: 77

WRN-related disorderTotal: 60

Wiskott-Aldrich syndromeTotal: 18

Ovarian cancerTotal: 13

CataractTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000553.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar	1 clinvar	25 clinvar	674 clinvar	2 clinvar	703
missense	2 clinvar	11 clinvar	1732 clinvar	55 clinvar	4 clinvar	1804
nonsense	78 clinvar	36 clinvar	3 clinvar	1 clinvar	1 clinvar	119
start loss			1 clinvar			1
frameshift	133 clinvar	61 clinvar	8 clinvar	2 clinvar		204
splice donor/acceptor (+/-2bp)	13 clinvar	100 clinvar	9 clinvar	1 clinvar	3 clinvar	126
Total	227	209	1778	733	10	2957

Highest pathogenic variant AF is 0.00025472417

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000553.6	RefSeq	NP_000544.2	34	MANE Select
ENST00000298139.7	Ensembl	ENSP00000298139.5	34	MANE Select
ENST00000650667.1	Ensembl	ENSP00000498593.1	3	Standard
ENST00000651642.1	Ensembl	ENSP00000498779.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

telomere maintenance
double-strand break repair via homologous recombination
DNA synthesis involved in DNA repair
replicative cell aging
DNA metabolic process

Molecular Function

magnesium ion binding
four-way junction DNA binding
Y-form DNA binding
bubble DNA binding
DNA binding

Cellular Component

chromosome, telomeric region
nucleus
nucleoplasm
replication fork
DNA replication factor A complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000298139
Coding exons: 34
Length: 139969
Individuals with no LoFs: 125609
Homozygous LoFs: 0
Heterozygous LoFs: 139
Defined: 125748
p: 0.000553

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.221	767	750	1.02	0.0000384	9508
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00061	0.00061	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.0015	0.0015	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00047	0.00047	rare
South Asian	0.00072	0.00072	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.523

Intolerance Scores

LoFtool: 0.988
RVIS EVS: 0.68
RVIS percentile EVS: 84.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0720

Gene Damage Prediction

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