WRAP53

protein-coding

WD repeat containing antisense to TP53, the group of WD repeat domain containing

Gene summary

This gene encodes an essential component of the telomerase holoenzyme complex, a ribonucleoprotein complex required for telomere synthesis. This protein is enriched in Cajal bodies, nuclear sites of RNP processing that are important for telomerase function. It interacts with dyskerin, TERT and TERC, other components of active telomerase, and with small Cajal body RNAs (scaRNAs), which are involved in modifying splicing RNAs. This mRNA also functions as a p53 antisense transcript, that regulates endogenous p53 mRNA levels and further induction of p53 protein by targeting the 5' untranslated region of p53 mRNA. Alternatively spliced transcript variants which differ only in the 5' UTR have been found for this gene. [provided by RefSeq, Mar 2011]

Previous symbols:

WDR79

MANE transcript

NM_001143992.2

Inheritance

AD, AR

ClinVar variants

P:11U:284B:161

Top phenotype

Dyskeratosis congenita, autosomal recessive 3

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr17:7,686,071-7,703,502

External References & Databases

Ensembl (ENSG00000141499)

Transcript & Mutation Effects

hg38 • Region Span ~17.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dyskeratosis congenitaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015780

Submitter: Orphanet

dyskeratosis congenita, autosomal recessive 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013520

Submitter: Labcorp Genetics (formerly Invitae)

dyskeratosis congenita, autosomal recessive 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013520

Submitter: Ambry Genetics

dyskeratosis congenita, autosomal recessive 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013520

Submitter: ClinGen

WD repeat-containing protein antisense to TP53 (WRAP53) was first reported in relation to a form of dyskeratosis congenita in 2011 (Zhong et al., PMID: 21205863). Individuals with *WRAP53* variants presented with features of the classic dyskeratosis congenita mucocutaneous triad (oral leukoplakia, nail dystrophy, abnormal skin pigmentation) in addition to more severe phenotypes that include but are not limited to, bone marrow failure, aplastic anemia, myelodysplastic syndrome. Short telomeres have been observed in all cases where telomere length was measured, and the age of onset ranges from very early childhood to adulthood. While interstitial lung disease (ILD) is associated with many telomere biology related diseases (PMID: 30540921), no cases with ILD were found in a literature search. There was however, one case reported to have a hepatopulmonary syndrome along with respiratory insufficiency (PMID: 37149759). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms or phenotypic variability. Therefore, the following disease entity has been curated as a single autosomal recessive disease entity. A single report was found that asserts a single case of aplastic anemia with short telomeres in a heterozygous WRAP53 variant carrier however further data are required to clarify that monoallelic *WRAP53* variant carriers can present with disease (PMID: 30523342 ). Cases have been reported in the literature with the severe form of telomere biology disorder referred to as Hoyeraal-Hreidarsson (PMID: 37149759). Other assertions have been made in the literature for Ewing sarcoma (PMID: 28125078), pediatric acute myeloid leukemia (PMID: 31470354), primary immunodeficiency (PMID: 32888943), craniometadiaphyseal dysplasia (PMID: 34484289), gastric cancer (PMID: 28875981), and breast cancer (PMID: 17683073); however, these additional assertions were split due to sequencing errors (PMID:36116037), presence of variants in other genes, and high allele frequencies. Ten missense variants that have been reported in 7 probands across 6 publications (PMIDs: 21205863, 29514627, 32303682, 34599657, 30552426, 37149759) are included in this curation. The mechanism of pathogenicity is reported to be a loss of function that results in shortened telomeres (PMID: 21205863). This gene-disease relationship is also supported by experimental evidence including biochemical function data that is consistent with the phenotype (PMID: 19179534), protein interactions with other genes known to cause dyskeratosis congenita (PMID: 32303682), functional alteration in iPSCs that demonstrate the human disease process (PMID: 21602826), and a cell culture model that displayed telomere shortening and the necessity of *WRAP53* for Cajal body formation (PMIDs: 19179534, 21072240). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on the meeting date March, 17 2026 (SOP Version 12). This gene-disease pair was originally evaluated by the General GCEP on January 25, 2017. It was reevaluated on March 17, 2026. As a result of this reevaluation, the classification did not change.

dyskeratosis congenita, autosomal recessive 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013520

Submitter: PanelApp Australia

dyskeratosis congenita, autosomal recessive 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013520

Submitter: G2P

Clinical Genomic Database (CGD)

Dyskeratosis congenita, autosomal recessive 3AR

Manifestation: Dermatologic; Hematologic; Oncologic; Pulmonary

Intervention: Hematologic; Oncologic; Pulmonary

Rationale: Surveillance (eg, with regularly performed CBC as well as other measures in the presence of concern for hematologic sequelae) for bone marrow failure, as well as surveillance for multiple cancer types (eg, with self-examination and clinical examination), and pulmonary disease may allow early detection and treatment; Lung transplant may be indicated in individuals with advanced lung diease; HSCT may be indicated due to manifestations including leukemia and bone marrow failure (which may also be treated with androgen therapy), but the long-term efficacy may not be optimal

Refs: 21205863; 20301779

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WRAP53 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 509

Dyskeratosis congenitaTotal: 97

Dyskeratosis congenita, autosomal recessive 3Total: 77

not specifiedTotal: 72

WRAP53-related disorderTotal: 20

Hereditary cancer-predisposing syndromeTotal: 3

Hereditary cancerTotal: 1

Malignant tumor of breastTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001143992.2. 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			4 clinvar	151 clinvar		155
missense	2 clinvar	4 clinvar	250 clinvar	9 clinvar	1 clinvar	266
nonsense		1 clinvar	6 clinvar			7
start loss			1 clinvar			1
frameshift	1 clinvar	3 clinvar	21 clinvar			25
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	3	8	284	160	1	456

Highest pathogenic variant AF is 0.00014810408

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001143992.2	RefSeq	NP_001137464.1	10	MANE Select
ENST00000396463.7	Ensembl	ENSP00000379727.3	10	MANE Select
NM_001143990.2	RefSeq	NP_001137462.1	10	Standard
NM_001143991.2	RefSeq	NP_001137463.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Chaperonin-mediated protein folding
Association of TriC/CCT with target proteins during biosynthesis
Telomere Extension By Telomerase
Extension of Telomeres

Biological Process

DNA repair
telomere maintenance via telomerase
Cajal body organization
telomere formation via telomerase
RNA folding

Molecular Function

RNA binding
protein binding
ubiquitin protein ligase binding
histone binding
identical protein binding

Cellular Component

chromosome, telomeric region
nucleoplasm
telomerase holoenzyme complex
cytosol
Cajal body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000316024
Coding exons: 10
Length: 17432
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0202	315	316	0.997	0.0000199	3543
Missense (PolyPhen)		109	121.68	0.89582		1291
Synonymous	-0.0817	129	128	1.01	0.00000823	1129
Loss of Function	2.82	12	28.2	0.426	0.00000179	271

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00024	0.00024	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: RNA chaperone that plays a key role in telomere maintenance and RNA localization to Cajal bodies (PubMed:29804836, PubMed:29695869). Specifically recognizes and binds the Cajal body box (CAB box) present in both small Cajal body RNAs (scaRNAs) and telomerase RNA template component (TERC) (PubMed:19285445, PubMed:20351177, PubMed:29804836, PubMed:29695869). Essential component of the telomerase holoenzyme complex, a ribonucleoprotein complex essential for the replication of chromosome termini that elongates telomeres in most eukaryotes (PubMed:19179534, PubMed:20351177, PubMed:26170453, PubMed:29695869). In the telomerase holoenzyme complex, required to stimulate the catalytic activity of the complex (PubMed:27525486, PubMed:29804836). Acts by specifically binding the CAB box of the TERC RNA and controlling the folding of the CR4/CR5 region of the TERC RNA, a critical step for telomerase activity (PubMed:29804836). In addition, also controls telomerase holoenzyme complex localization to Cajal body (PubMed:22547674). During S phase, required for delivery of TERC to telomeres during S phase and for telomerase activity (PubMed:29804836). In addition to its role in telomere maintenance, also required for Cajal body formation, probably by mediating localization of scaRNAs to Cajal bodies (PubMed:19285445, PubMed:21072240). Also plays a role in DNA repair: phosphorylated by ATM in response to DNA damage and relocalizes to sites of DNA double-strand breaks to promote the repair of DNA double-strand breaks (PubMed:25512560, PubMed:27715493). Acts by recruiting the ubiquitin ligase RNF8 to DNA breaks and promote both homologous recombination (HR) and non- homologous end joining (NHEJ) (PubMed:25512560, PubMed:27715493). {ECO:0000269|PubMed:19179534, ECO:0000269|PubMed:19285445, ECO:0000269|PubMed:20351177, ECO:0000269|PubMed:21072240, ECO:0000269|PubMed:22547674, ECO:0000269|PubMed:25512560, ECO:0000269|PubMed:26170453, ECO:0000269|PubMed:27525486, ECO:0000269|PubMed:27715493, ECO:0000269|PubMed:29695869, ECO:0000269|PubMed:29804836}.;
Disease: DISEASE: Dyskeratosis congenita, autosomal recessive, 3 (DKCB3) [MIM:613988]: A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. {ECO:0000269|PubMed:21205863, ECO:0000269|PubMed:21602826}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.759
RVIS EVS: -0.57
RVIS percentile EVS: 18.9

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.649

Gene Damage Prediction

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