rs73248508

chr17-7701770-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001143992.2(WRAP53):c.936C>T(p.Cys312=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,613,614 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (13 hom.)
• Consequence: WRAP53 NM_001143992.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.07

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=-0.38).
• BP6: Variant 17-7701770-C-T is Benign according to our data. Variant chr17-7701770-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 325659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7701770-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00524 (798/152338) while in subpopulation AFR AF= 0.0143 (596/41588). AF 95% confidence interval is 0.0134. There are 2 homozygotes in gnomad4. There are 373 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRAP53	NM_001143992.2	c.936C>T	p.Cys312=	synonymous_variant	7/11	ENST00000396463.7
WRAP53	NM_001143990.2	c.936C>T	p.Cys312=	synonymous_variant	7/11
WRAP53	NM_001143991.2	c.936C>T	p.Cys312=	synonymous_variant	7/11
WRAP53	NM_018081.2	c.936C>T	p.Cys312=	synonymous_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRAP53	ENST00000396463.7	c.936C>T	p.Cys312=	synonymous_variant	7/11	1	NM_001143992.2	P1

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 796 AN: 152220 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00207 AC: 516 AN: 248954 Hom.: 2 AF XY: 0.00176 AC XY: 237 AN XY: 135020

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000842

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000393

Gnomad FIN exome AF: 0.000420

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00240 AC: 3507 AN: 1461276 Hom.: 13 Cov.: 32 AF XY: 0.00228 AC XY: 1658 AN XY: 726950

Gnomad4 AFR exome AF: 0.0161

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000569

Gnomad4 FIN exome AF: 0.000508

Gnomad4 NFE exome AF: 0.00239

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.00524 AC: 798 AN: 152338 Hom.: 2 Cov.: 32 AF XY: 0.00501 AC XY: 373 AN XY: 74476

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00355 Hom.: 1

Bravo AF: 0.00578

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 18, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2022

This alteration is classified as likely 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	-0.38
Cadd	Benign	1.5
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73248508; hg19: chr17-7605088; COSMIC: COSV56833082; COSMIC: COSV56833082;