17-7703480-G-T

Variant names:

• chr17-7703480-G-T
• rs146994329
• NM_001143992.2:c.1641G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001143992.2(WRAP53):​c.1641G>T​(p.Leu547Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000934 in 1,608,066 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (8 hom., cov: 29)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: WRAP53 NM_001143992.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.237
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-7703480-G-T is Benign according to our data. Variant chr17-7703480-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.237 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00483 (729/150912) while in subpopulation AFR AF = 0.0166 (680/40892). AF 95% confidence interval is 0.0156. There are 8 homozygotes in GnomAd4. There are 360 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143992.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRAP53	NM_001143992.2	MANE Select	c.1641G>T	p.Leu547Leu	synonymous	Exon 11 of 11	NP_001137464.1
	WRAP53	NM_001143990.2		c.1641G>T	p.Leu547Leu	synonymous	Exon 11 of 11	NP_001137462.1
	WRAP53	NM_001143991.2		c.1641G>T	p.Leu547Leu	synonymous	Exon 11 of 11	NP_001137463.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRAP53	ENST00000396463.7	TSL:1 MANE Select	c.1641G>T	p.Leu547Leu	synonymous	Exon 11 of 11	ENSP00000379727.3
	WRAP53	ENST00000316024.9	TSL:1	c.1641G>T	p.Leu547Leu	synonymous	Exon 10 of 10	ENSP00000324203.5
	WRAP53	ENST00000431639.6	TSL:1	c.1641G>T	p.Leu547Leu	synonymous	Exon 11 of 11	ENSP00000397219.2

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 726 AN: 150788 Hom.: 8 Cov.: 29

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00258

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00141 AC: 354 AN: 250732 AF XY: 0.000995

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000530 AC: 773 AN: 1457154 Hom.: 1 Cov.: 40 AF XY: 0.000432 AC XY: 313 AN XY: 724990

African (AFR) AF: 0.0179 AC: 593 AN: 33058

American (AMR) AF: 0.00182 AC: 81 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 38946

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52832

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5752

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109738

Other (OTH) AF: 0.00141 AC: 85 AN: 60076

GnomAD4 genome AF: 0.00483 AC: 729 AN: 150912 Hom.: 8 Cov.: 29 AF XY: 0.00488 AC XY: 360 AN XY: 73716

African (AFR) AF: 0.0166 AC: 680 AN: 40892

American (AMR) AF: 0.00258 AC: 39 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67856

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.00229 Hom.: 1

Bravo AF: 0.00589

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 17, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 20, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dyskeratosis congenita Benign:1

Feb 17, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.70
DANN	Benign	0.64
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs146994329; hg19: chr17-7606798;