17-7688404-G-C

Position:

• chr17-7688404-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000316024.9(WRAP53):​c.-245G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 558,102 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (57 hom., cov: 32)
  • Exomes 𝑓: 0.026 (221 hom.)
• Consequence: WRAP53 ENST00000316024.9 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.808

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-7688404-G-C is Benign according to our data. Variant chr17-7688404-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 369235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7688404-G-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRAP53	NM_018081.2	c.-245G>C		5_prime_UTR_variant	1/10
WRAP53	NM_001143990.2	c.-1-244G>C		intron_variant
WRAP53	NM_001143991.2	c.-1-244G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRAP53	ENST00000316024.9	c.-245G>C		5_prime_UTR_variant	1/10	1		P1
WRAP53	ENST00000431639.6	c.-1-244G>C		intron_variant		1		P1
WRAP53	ENST00000457584.6	c.-1-244G>C		intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3394 AN: 152212 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.00822

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0337

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0478

GnomAD4 exome AF: 0.0258 AC: 10489 AN: 405772 Hom.: 221 Cov.: 3 AF XY: 0.0254 AC XY: 5420 AN XY: 213198

Gnomad4 AFR exome AF: 0.00772

Gnomad4 AMR exome AF: 0.0302

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.0000728

Gnomad4 SAS exome AF: 0.00849

Gnomad4 FIN exome AF: 0.0286

Gnomad4 NFE exome AF: 0.0261

Gnomad4 OTH exome AF: 0.0376

GnomAD4 genome AF: 0.0223 AC: 3392 AN: 152330 Hom.: 57 Cov.: 32 AF XY: 0.0230 AC XY: 1715 AN XY: 74488

Gnomad4 AFR AF: 0.00822

Gnomad4 AMR AF: 0.0336

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.0247

Gnomad4 OTH AF: 0.0473

Alfa AF: 0.00508 Hom.: 2

Bravo AF: 0.0243

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	8.8
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17883670; hg19: chr17-7591722;