rs2287497

Variant names:

• chr17-7689462-G-A
• rs2287497
• NM_001143992.2:c.531-128G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001143992.2(WRAP53):​c.531-128G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,246,102 control chromosomes in the GnomAD database, including 21,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (7725 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13397 hom.)
• Consequence: WRAP53 NM_001143992.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.439
• Publications: 29 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-7689462-G-A is Benign according to our data. Variant chr17-7689462-G-A is described in ClinVar as Benign. ClinVar VariationId is 1258203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRAP53	NM_001143992.2	c.531-128G>A		intron_variant	Intron 3 of 10	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2	c.531-128G>A		intron_variant	Intron 3 of 10		NP_001137462.1
WRAP53	NM_001143991.2	c.531-128G>A		intron_variant	Intron 3 of 10		NP_001137463.1
WRAP53	NM_018081.2	c.531-128G>A		intron_variant	Intron 2 of 9		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7	c.531-128G>A		intron_variant	Intron 3 of 10	1	NM_001143992.2	ENSP00000379727.3

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37400 AN: 151778 Hom.: 7714 Cov.: 32

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.0591

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.126 AC: 137724 AN: 1094204 Hom.: 13397 Cov.: 15 AF XY: 0.128 AC XY: 71484 AN XY: 556792

African (AFR) AF: 0.570 AC: 14745 AN: 25858

American (AMR) AF: 0.180 AC: 6694 AN: 37286

Ashkenazi Jewish (ASJ) AF: 0.0930 AC: 2176 AN: 23388

East Asian (EAS) AF: 0.282 AC: 10495 AN: 37234

South Asian (SAS) AF: 0.233 AC: 17613 AN: 75628

European-Finnish (FIN) AF: 0.0591 AC: 2981 AN: 50446

Middle Eastern (MID) AF: 0.149 AC: 749 AN: 5014

European-Non Finnish (NFE) AF: 0.0949 AC: 75047 AN: 791210

Other (OTH) AF: 0.150 AC: 7224 AN: 48140

GnomAD4 genome AF: 0.247 AC: 37443 AN: 151898 Hom.: 7725 Cov.: 32 AF XY: 0.242 AC XY: 17960 AN XY: 74268

African (AFR) AF: 0.564 AC: 23336 AN: 41348

American (AMR) AF: 0.191 AC: 2907 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 336 AN: 3470

East Asian (EAS) AF: 0.308 AC: 1588 AN: 5154

South Asian (SAS) AF: 0.226 AC: 1087 AN: 4814

European-Finnish (FIN) AF: 0.0591 AC: 625 AN: 10578

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 7008 AN: 67972

Other (OTH) AF: 0.211 AC: 445 AN: 2112

Alfa AF: 0.141 Hom.: 5117

Bravo AF: 0.269

Asia WGS AF: 0.275 AC: 955 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.5
DANN	Benign	0.67
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism (auto)

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: rs2287497; hg19: chr17-7592780;