rs34016213

Variant names:

• chr17-7703032-T-C
• rs34016213
• NM_001143992.2:c.1308T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001143992.2(WRAP53):​c.1308T>C​(p.Ala436Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,004 control chromosomes in the GnomAD database, including 834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (431 hom., cov: 31)
  • Exomes 𝑓: 0.0089 (403 hom.)
• Consequence: WRAP53 NM_001143992.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.27

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 17-7703032-T-C is Benign according to our data. Variant chr17-7703032-T-C is described in ClinVar as [Benign]. Clinvar id is 260996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7703032-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRAP53	NM_001143992.2	c.1308T>C	p.Ala436Ala	synonymous_variant	Exon 10 of 11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2	c.1308T>C	p.Ala436Ala	synonymous_variant	Exon 10 of 11		NP_001137462.1
WRAP53	NM_001143991.2	c.1308T>C	p.Ala436Ala	synonymous_variant	Exon 10 of 11		NP_001137463.1
WRAP53	NM_018081.2	c.1308T>C	p.Ala436Ala	synonymous_variant	Exon 9 of 10		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7	c.1308T>C	p.Ala436Ala	synonymous_variant	Exon 10 of 11	1	NM_001143992.2	ENSP00000379727.3

Frequencies

GnomAD3 genomes AF: 0.0448 AC: 6807 AN: 152046 Hom.: 430 Cov.: 31

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00810

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0147 AC: 3702 AN: 251352 Hom.: 171 AF XY: 0.0117 AC XY: 1589 AN XY: 135874

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00820

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00510

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00885 AC: 12943 AN: 1461840 Hom.: 403 Cov.: 33 AF XY: 0.00827 AC XY: 6016 AN XY: 727212

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00879

Gnomad4 FIN exome AF: 0.00157

Gnomad4 NFE exome AF: 0.00515

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0448 AC: 6824 AN: 152164 Hom.: 431 Cov.: 31 AF XY: 0.0434 AC XY: 3232 AN XY: 74406

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.0261

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00769

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00529

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0179 Hom.: 95

Bravo AF: 0.0512

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00610

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 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

Oct 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita Benign:1

Jun 29, 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	-0.92
CADD	Benign	0.11
DANN	Benign	0.35

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

Other links and lift over

dbSNP: rs34016213; hg19: chr17-7606350; COSMIC: COSV56834677; COSMIC: COSV56834677;