rs2287499

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001143992.2(WRAP53):c.202C>G(p.Arg68Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,614,002 control chromosomes in the GnomAD database, including 38,182 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 13477 hom., cov: 32)

Exomes 𝑓: 0.14 ( 24705 hom. )

Consequence

WRAP53
NM_001143992.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.419

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]

WRAP53 links:

WRAP53 (HGNC:):

WRAP53 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.1231465E-7).

BP6

Variant 17-7688850-C-G is Benign according to our data. Variant chr17-7688850-C-G is described in ClinVar as [Benign]. Clinvar id is 261001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7688850-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRAP53	NM_001143992.2 linkuse as main transcript	c.202C>G	p.Arg68Gly	missense_variant	2/11	ENST00000396463.7	NP_001137464.1	Q9BUR4
WRAP53	NM_001143990.2 linkuse as main transcript	c.202C>G	p.Arg68Gly	missense_variant	2/11		NP_001137462.1	Q9BUR4
WRAP53	NM_001143991.2 linkuse as main transcript	c.202C>G	p.Arg68Gly	missense_variant	2/11		NP_001137463.1	Q9BUR4
WRAP53	NM_018081.2 linkuse as main transcript	c.202C>G	p.Arg68Gly	missense_variant	1/10		NP_060551.2	Q9BUR4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7 linkuse as main transcript	c.202C>G	p.Arg68Gly	missense_variant	2/11	1	NM_001143992.2	ENSP00000379727.3		Q9BUR4

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

47352

AN:

151998

Hom.:

13437

Cov.:

show subpopulations

Gnomad AFR

AF:

0.757

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.113

Gnomad EAS

AF:

0.307

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.0622

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.266

GnomAD3 exomes

AF:

0.199

AC:

50003

AN:

250972

Hom.:

8615

AF XY:

0.190

AC XY:

25800

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.773

Gnomad AMR exome

AF:

0.202

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.309

Gnomad SAS exome

AF:

0.262

Gnomad FIN exome

AF:

0.0609

Gnomad NFE exome

AF:

0.118

Gnomad OTH exome

AF:

0.163

GnomAD4 exome

AF:

0.144

AC:

211092

AN:

1461884

Hom.:

24705

Cov.:

AF XY:

0.146

AC XY:

106161

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.783

Gnomad4 AMR exome

AF:

0.205

Gnomad4 ASJ exome

AF:

0.111

Gnomad4 EAS exome

AF:

0.285

Gnomad4 SAS exome

AF:

0.260

Gnomad4 FIN exome

AF:

0.0643

Gnomad4 NFE exome

AF:

0.111

Gnomad4 OTH exome

AF:

0.178

GnomAD4 genome

AF:

0.312

AC:

47448

AN:

152118

Hom.:

13477

Cov.:

AF XY:

0.306

AC XY:

22739

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.758

Gnomad4 AMR

AF:

0.228

Gnomad4 ASJ

AF:

0.113

Gnomad4 EAS

AF:

0.307

Gnomad4 SAS

AF:

0.252

Gnomad4 FIN

AF:

0.0622

Gnomad4 NFE

AF:

0.118

Gnomad4 OTH

AF:

0.267

Alfa

AF:

0.124

Hom.:

1272

Bravo

AF:

0.341

TwinsUK

AF:

0.110

AC:

408

ALSPAC

AF:

0.116

AC:

446

ESP6500AA

AF:

0.741

AC:

3265

ESP6500EA

AF:

0.116

AC:

998

ExAC

AF:

0.212

AC:

25704

Asia WGS

AF:

0.303

AC:

1051

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, variant associated with breast cancer -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 29% of patients studied by a panel of primary immunodeficiencies. Number of patients: 28. Only high quality variants are reported. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 25134915, 17683073) -

Dyskeratosis congenita, autosomal recessive 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Li-Fraumeni syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dyskeratosis congenita

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.71

CADD

Benign

9.9

DANN

Benign

0.61

DEOGEN2

Benign

0.0057

T;T;T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0030

LIST_S2

Benign

0.11

.;.;.;T;T

MetaRNN

Benign

9.1e-7

T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.23

PROVEAN

Benign

0.36

N;N;N;N;N

REVEL

Benign

0.041

Sift

Benign

0.80

T;T;T;T;T

Sift4G

Benign

0.46

T;T;T;T;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.059

MPC

0.31

ClinPred

0.0018

GERP RS

1.1

Varity_R

0.040

gMVP

0.11

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over