17-7703396-TG-TGG

Position:

• chr17-7703396-TG-TGG

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_001143992.2(WRAP53):​c.1564dupG​(p.Ala522fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000883 in 1,606,146 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A522A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00089 (2 hom.)
• Consequence: WRAP53 NM_001143992.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 1.81

Genes affected

WRAP53 (HGNC:25522): (WD repeat containing antisense to TP53) 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]

WRAP53 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0498 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRAP53	NM_001143992.2	c.1564dupG	p.Ala522fs	frameshift_variant	11/11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2	c.1564dupG	p.Ala522fs	frameshift_variant	11/11		NP_001137462.1
WRAP53	NM_001143991.2	c.1564dupG	p.Ala522fs	frameshift_variant	11/11		NP_001137463.1
WRAP53	NM_018081.2	c.1564dupG	p.Ala522fs	frameshift_variant	10/10		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7	c.1564dupG	p.Ala522fs	frameshift_variant	11/11	1	NM_001143992.2	ENSP00000379727.3

Frequencies

GnomAD3 genomes AF: 0.000773 AC: 116 AN: 150052 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000740

Gnomad OTH AF: 0.000974

GnomAD4 exome AF: 0.000894 AC: 1302 AN: 1455980 Hom.: 2 Cov.: 34 AF XY: 0.000900 AC XY: 652 AN XY: 724366

Gnomad4 AFR exome AF: 0.000830

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.00195

Gnomad4 NFE exome AF: 0.000916

Gnomad4 OTH exome AF: 0.000732

GnomAD4 genome AF: 0.000772 AC: 116 AN: 150166 Hom.: 0 Cov.: 31 AF XY: 0.000791 AC XY: 58 AN XY: 73344

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00193

Gnomad4 NFE AF: 0.000740

Gnomad4 OTH AF: 0.000963

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2020	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 12, 2023	PVS1_moderate -

Dyskeratosis congenita, autosomal recessive 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 25, 2022	- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 07, 2022

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. -

Dyskeratosis congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs755116516; hg19: chr17-7606714;