rs755116516

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The ENST00000396463.7(WRAP53):​c.1564del​(p.Ala522ArgfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000591 in 1,607,406 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (β˜…β˜…). Synonymous variant affecting the same amino acid position (i.e. G520G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000062 ( 1 hom. )

Consequence

WRAP53
ENST00000396463.7 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.81
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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 0.054 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WRAP53NM_001143992.2 linkuse as main transcriptc.1564del p.Ala522ArgfsTer26 frameshift_variant 11/11 ENST00000396463.7 NP_001137464.1
WRAP53NM_001143990.2 linkuse as main transcriptc.1564del p.Ala522ArgfsTer26 frameshift_variant 11/11 NP_001137462.1
WRAP53NM_001143991.2 linkuse as main transcriptc.1564del p.Ala522ArgfsTer26 frameshift_variant 11/11 NP_001137463.1
WRAP53NM_018081.2 linkuse as main transcriptc.1564del p.Ala522ArgfsTer26 frameshift_variant 10/10 NP_060551.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WRAP53ENST00000396463.7 linkuse as main transcriptc.1564del p.Ala522ArgfsTer26 frameshift_variant 11/111 NM_001143992.2 ENSP00000379727 P1

Frequencies

GnomAD3 genomes
AF:
0.0000267
AC:
4
AN:
150064
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000789
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000100
AC:
25
AN:
249660
Hom.:
0
AF XY:
0.0000739
AC XY:
10
AN XY:
135262
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00120
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000624
AC:
91
AN:
1457342
Hom.:
1
Cov.:
34
AF XY:
0.0000593
AC XY:
43
AN XY:
725042
show subpopulations
Gnomad4 AFR exome
AF:
0.0000305
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00188
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000267
AC:
4
AN:
150064
Hom.:
0
Cov.:
31
AF XY:
0.0000410
AC XY:
3
AN XY:
73228
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000789
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal recessive 3 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 28, 2022- -
Uncertain significance, criteria provided, single submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 31, 2022This sequence change creates a premature translational stop signal (p.Ala522Argfs*26) 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. This variant is present in population databases (rs755116516, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with WRAP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 225516). 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, no assertion criteria providedresearchCenter of Medical Genetics and Primary Health CareApr 08, 2020ACMG Guidelines 2015 criteria PP3 Pathogenic Supporting: 1 pathogenic prediction from GERP vs no benign predictions. BS1 Benign Strong: GnomAD exomes East Asian allele frequency = 0.0012 > 0.000528 derived from the 60 clinically reported variants in gene WRAP53 of which 2 PATH, 25 VUS and 33 BEN. Therefore, this variant was classified as a Variant of Unknown Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755116516; hg19: chr17-7606714; API