17-7703404-C-G

Position:

chr17-7703404-C-G

Variant summary

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

The NM_001143992.2(WRAP53):c.1565C>G(p.Ala522Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,613,258 control chromosomes in the GnomAD database, including 69,315 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A522V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.40 ( 17179 hom., cov: 30)

Exomes 𝑓: 0.24 ( 52136 hom. )

Consequence

WRAP53
NM_001143992.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.39

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:

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=9.1508036E-7).

BP6

Variant 17-7703404-C-G is Benign according to our data. Variant chr17-7703404-C-G is described in ClinVar as [Benign]. Clinvar id is 260999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7703404-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
WRAP53	NM_001143992.2 linkuse as main transcript	c.1565C>G	p.Ala522Gly	missense_variant	11/11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2 linkuse as main transcript	c.1565C>G	p.Ala522Gly	missense_variant	11/11		NP_001137462.1
WRAP53	NM_001143991.2 linkuse as main transcript	c.1565C>G	p.Ala522Gly	missense_variant	11/11		NP_001137463.1
WRAP53	NM_018081.2 linkuse as main transcript	c.1565C>G	p.Ala522Gly	missense_variant	10/10		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7 linkuse as main transcript	c.1565C>G	p.Ala522Gly	missense_variant	11/11	1	NM_001143992.2	ENSP00000379727	P1

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

59935

AN:

151452

Hom.:

17124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.811

Gnomad AMI

AF:

0.241

Gnomad AMR

AF:

0.283

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.428

Gnomad SAS

AF:

0.434

Gnomad FIN

AF:

0.211

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.208

Gnomad OTH

AF:

0.336

GnomAD3 exomes

AF:

0.299

AC:

75127

AN:

250874

Hom.:

14713

AF XY:

0.294

AC XY:

39953

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.825

Gnomad AMR exome

AF:

0.266

Gnomad ASJ exome

AF:

0.199

Gnomad EAS exome

AF:

0.421

Gnomad SAS exome

AF:

0.446

Gnomad FIN exome

AF:

0.206

Gnomad NFE exome

AF:

0.205

Gnomad OTH exome

AF:

0.256

GnomAD4 exome

AF:

0.241

AC:

352359

AN:

1461688

Hom.:

52136

Cov.:

AF XY:

0.245

AC XY:

178100

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.835

Gnomad4 AMR exome

AF:

0.268

Gnomad4 ASJ exome

AF:

0.195

Gnomad4 EAS exome

AF:

0.394

Gnomad4 SAS exome

AF:

0.435

Gnomad4 FIN exome

AF:

0.209

Gnomad4 NFE exome

AF:

0.203

Gnomad4 OTH exome

AF:

0.270

GnomAD4 genome

AF:

0.396

AC:

60067

AN:

151570

Hom.:

17179

Cov.:

AF XY:

0.394

AC XY:

29176

AN XY:

74040

show subpopulations

Gnomad4 AFR

AF:

0.812

Gnomad4 AMR

AF:

0.283

Gnomad4 ASJ

AF:

0.197

Gnomad4 EAS

AF:

0.428

Gnomad4 SAS

AF:

0.434

Gnomad4 FIN

AF:

0.211

Gnomad4 NFE

AF:

0.208

Gnomad4 OTH

AF:

0.341

Alfa

AF:

0.212

Hom.:

2564

Bravo

AF:

0.417

TwinsUK

AF:

0.199

AC:

738

ALSPAC

AF:

0.203

AC:

781

ESP6500AA

AF:

0.788

AC:

3470

ESP6500EA

AF:

0.195

AC:

1675

ExAC

AF:

0.313

AC:

37967

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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 40% of patients studied by a panel of primary immunodeficiencies. Number of patients: 38. Only high quality variants are reported. -

not provided

Benign:3

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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dyskeratosis congenita, autosomal recessive 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

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

0.057

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.0090

DANN

Benign

0.62

DEOGEN2

Benign

0.0067

T;T;T;T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00050

LIST_S2

Benign

0.14

.;.;.;T;T

MetaRNN

Benign

9.2e-7

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.040

N;N;N;N;N

REVEL

Benign

0.024

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.016

MPC

0.24

ClinPred

0.0045

GERP RS

-6.6

Varity_R

0.017

gMVP

0.25

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