rs2287498

Positions:

• chr17-7689242-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001143992.2(WRAP53):​c.450C>T​(p.Phe150=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0979 in 1,613,714 control chromosomes in the GnomAD database, including 10,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1982 hom., cov: 31)
  • Exomes 𝑓: 0.094 (8891 hom.)
• Consequence: WRAP53 NM_001143992.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.513

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 17-7689242-C-T is Benign according to our data. Variant chr17-7689242-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7689242-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.513 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRAP53	NM_001143992.2	c.450C>T	p.Phe150=	synonymous_variant	3/11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2	c.450C>T	p.Phe150=	synonymous_variant	3/11		NP_001137462.1
WRAP53	NM_001143991.2	c.450C>T	p.Phe150=	synonymous_variant	3/11		NP_001137463.1
WRAP53	NM_018081.2	c.450C>T	p.Phe150=	synonymous_variant	2/10		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7	c.450C>T	p.Phe150=	synonymous_variant	3/11	1	NM_001143992.2	ENSP00000379727	P1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21144 AN: 151774 Hom.: 1980 Cov.: 31

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.0807

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.0471

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0757

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.130 AC: 32768 AN: 251470 Hom.: 3024 AF XY: 0.130 AC XY: 17623 AN XY: 135916

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.0788

Gnomad EAS exome AF: 0.308

Gnomad SAS exome AF: 0.222

Gnomad FIN exome AF: 0.0453

Gnomad NFE exome AF: 0.0755

Gnomad OTH exome AF: 0.0989

GnomAD4 exome AF: 0.0935 AC: 136744 AN: 1461822 Hom.: 8891 Cov.: 33 AF XY: 0.0967 AC XY: 70342 AN XY: 727226

Gnomad4 AFR exome AF: 0.251

Gnomad4 AMR exome AF: 0.149

Gnomad4 ASJ exome AF: 0.0783

Gnomad4 EAS exome AF: 0.284

Gnomad4 SAS exome AF: 0.218

Gnomad4 FIN exome AF: 0.0467

Gnomad4 NFE exome AF: 0.0718

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.139 AC: 21164 AN: 151892 Hom.: 1982 Cov.: 31 AF XY: 0.140 AC XY: 10388 AN XY: 74256

Gnomad4 AFR AF: 0.247

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.0807

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.0471

Gnomad4 NFE AF: 0.0757

Gnomad4 OTH AF: 0.125

Alfa AF: 0.0881 Hom.: 1513

Bravo AF: 0.148

Asia WGS AF: 0.251 AC: 869 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

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 -
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 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -
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	-	- -

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	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Li-Fraumeni syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Oct 08, 2015

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
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.0
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2287498; hg19: chr17-7592560; COSMIC: COSV52807243; COSMIC: COSV52807243;