Submissions for variant NM_001143992.2(WRAP53):c.1564dup (p.Ala522fs)

dbSNP: rs755116516

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045892	SCV001209766	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala522Glyfs*8) in the WRAP53 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the WRAP53 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with medulloblastoma and Ewing sarcoma (PMID: 26822237, 28125078). ClinVar contains an entry for this variant (Variation ID: 843298). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001045892	SCV001794202	uncertain significance	not provided	2020-07-16	criteria provided, single submitter	clinical testing	Identified in a patient with medulloblastoma as a heterozygous finding in the presence of variants in additional genes in published literature (Parsons et al., 2016); Identified using alternate nomenclature (c.1558dupG) in an individual with Ewing sarcoma (Brohl et al., 2017); Frameshift variant predicted to result in protein truncation as the last 27 amino acids are lost and replaced with 7 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 28125078, 26822237)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002053129	SCV002320664	uncertain significance	Dyskeratosis congenita, autosomal recessive 3	2021-03-30	criteria provided, single submitter	clinical testing	WRAP53 NM_018081.2 exon 10 p.Ala522Glyfs*8 (c.1564dup): This variant has been reported in the literature in at least 2 individuals (1 with medulloblastoma, 1 with Ewing sarcoma) (Parsons 2016 PMID:26822237, Brohl 2017 PMID:28125078). This variant is present in 0.2% (52/24402) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-7606714-T-TG). This variant is present in ClinVar (Variation ID:843298). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a duplication of 1 nucleotide at position 1564 and creates a premature stop codon 8 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in the literature but this mechanism has not been definitively established in association with disease. In addition, this variant occurs within the last exon of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Ambry Genetics	RCV002400262	SCV002707725	uncertain significance	Dyskeratosis congenita	2017-01-05	criteria provided, single submitter	clinical testing	The c.1564dupG variant, located in coding exon 10 of the WRAP53 gene, results from a duplication of G at nucleotide position 1564, causing a translational frameshift with a predicted alternate stop codon (p.A522Gfs*8). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of WRAP53, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 28 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. Based on available evidence to date, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002053129	SCV002789671	uncertain significance	Dyskeratosis congenita, autosomal recessive 3	2024-05-30	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001045892	SCV005192666	uncertain significance	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV001045892	SCV005412637	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	PVS1_moderate
Genetic Services Laboratory, University of Chicago	RCV003151271	SCV003839227	uncertain significance	not specified	2022-03-07	no assertion criteria provided	clinical testing	DNA sequence analysis of the WRAP53 gene demonstrated a one base pair duplication in exon 10, c.1564dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 8 amino acids downstream of the change, p.Ala522Glyfs*8. This sequence change is predicted to result in an abnormal transcript, which is not expected to undergo nonsense mediated decay, but may lead to the production of a truncated WRAP53 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.21% in the African/African American subpopulation (dbSNP rs766557841), however, the quality metrics for this region indicate that frequency data may not be reliable. This sequence change has previously been described in an individual with Ewing sarcoma and in an individual with medulloblastoma (PMID: 28125078, 26822237). The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined.