17-7689242-C-T

Variant names:

• chr17-7689242-C-T
• rs2287498
• NM_001143992.2:c.450C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001143992.2(WRAP53):​c.450C>T​(p.Phe150Phe) 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
• Publications: 44 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 261003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
WRAP53	NM_001143992.2	c.450C>T	p.Phe150Phe	synonymous_variant	Exon 3 of 11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2	c.450C>T	p.Phe150Phe	synonymous_variant	Exon 3 of 11		NP_001137462.1
WRAP53	NM_001143991.2	c.450C>T	p.Phe150Phe	synonymous_variant	Exon 3 of 11		NP_001137463.1
WRAP53	NM_018081.2	c.450C>T	p.Phe150Phe	synonymous_variant	Exon 2 of 10		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7	c.450C>T	p.Phe150Phe	synonymous_variant	Exon 3 of 11	1	NM_001143992.2	ENSP00000379727.3

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

GnomAD2 exomes AF: 0.130 AC: 32768 AN: 251470 AF XY: 0.130

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 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

African (AFR) AF: 0.251 AC: 8392 AN: 33476

American (AMR) AF: 0.149 AC: 6683 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0783 AC: 2045 AN: 26134

East Asian (EAS) AF: 0.284 AC: 11282 AN: 39698

South Asian (SAS) AF: 0.218 AC: 18812 AN: 86250

European-Finnish (FIN) AF: 0.0467 AC: 2496 AN: 53414

Middle Eastern (MID) AF: 0.0922 AC: 532 AN: 5768

European-Non Finnish (NFE) AF: 0.0718 AC: 79827 AN: 1111968

Other (OTH) AF: 0.111 AC: 6675 AN: 60392

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

African (AFR) AF: 0.247 AC: 10195 AN: 41350

American (AMR) AF: 0.140 AC: 2128 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0807 AC: 280 AN: 3468

East Asian (EAS) AF: 0.304 AC: 1565 AN: 5146

South Asian (SAS) AF: 0.212 AC: 1011 AN: 4776

European-Finnish (FIN) AF: 0.0471 AC: 500 AN: 10608

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0757 AC: 5147 AN: 67982

Other (OTH) AF: 0.125 AC: 263 AN: 2110

Alfa AF: 0.0968 Hom.: 3953

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:3

-

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 -

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

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita, autosomal recessive 3 Benign:2

Jan 13, 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. -

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita Benign:1

Oct 08, 2015

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
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.0
DANN	Benign	0.71
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2287498; hg19: chr17-7592560; COSMIC: COSV52807243; COSMIC: COSV52807243;