rs2287499

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R68P) has been classified as Uncertain significance.

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

Publications

81 publications found

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 Gene-Disease associations (from GenCC):

dyskeratosis congenita, autosomal recessive 3
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
dyskeratosis congenita
Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

WRAP53 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 261001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
WRAP53	NM_001143992.2 link	c.202C>G	p.Arg68Gly	missense_variant	Exon 2 of 11	ENST00000396463.7	NP_001137464.1	Q9BUR4
WRAP53	NM_001143990.2 link	c.202C>G	p.Arg68Gly	missense_variant	Exon 2 of 11		NP_001137462.1	Q9BUR4
WRAP53	NM_001143991.2 link	c.202C>G	p.Arg68Gly	missense_variant	Exon 2 of 11		NP_001137463.1	Q9BUR4
WRAP53	NM_018081.2 link	c.202C>G	p.Arg68Gly	missense_variant	Exon 1 of 10		NP_060551.2	Q9BUR4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7 link	c.202C>G	p.Arg68Gly	missense_variant	Exon 2 of 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

GnomAD2 exomes

AF:

0.199

AC:

50003

AN:

250972

AF XY:

0.190

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 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

African (AFR)

AF:

0.783

AC:

26218

AN:

33480

American (AMR)

AF:

0.205

AC:

9173

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

2899

AN:

26136

East Asian (EAS)

AF:

0.285

AC:

11308

AN:

39700

South Asian (SAS)

AF:

0.260

AC:

22470

AN:

86258

European-Finnish (FIN)

AF:

0.0643

AC:

3434

AN:

53412

Middle Eastern (MID)

AF:

0.182

AC:

1049

AN:

5768

European-Non Finnish (NFE)

AF:

0.111

AC:

123787

AN:

1112010

Other (OTH)

AF:

0.178

AC:

10754

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

11970

23940

35910

47880

59850

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4922

9844

14766

19688

24610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.312

AC:

47448

AN:

152118

Hom.:

13477

Cov.:

AF XY:

0.306

AC XY:

22739

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.758

AC:

31420

AN:

41478

American (AMR)

AF:

0.228

AC:

3479

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

393

AN:

3472

East Asian (EAS)

AF:

0.307

AC:

1587

AN:

5168

South Asian (SAS)

AF:

0.252

AC:

1218

AN:

4824

European-Finnish (FIN)

AF:

0.0622

AC:

659

AN:

10600

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8010

AN:

67984

Other (OTH)

AF:

0.267

AC:

562

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1076

2152

3227

4303

5379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

394

788

1182

1576

1970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:3

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Dyskeratosis congenita, autosomal recessive 3

Benign:3

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25134915, 17683073) -

Li-Fraumeni syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita

Benign:1

Dec 17, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

0.42

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

PromoterAI

0.0042

Neutral

(source)

Varity_R

0.040

gMVP

0.11

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over