17-7703396-TG-TGG

Variant names:

• chr17-7703396-T-TG
• rs755116516
• NM_001143992.2:c.1564dupG

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BS1_Supporting BS2

The NM_001143992.2(WRAP53):​c.1564dupG​(p.Ala522GlyfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000883 in 1,606,146 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A522A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00089 (2 hom.)
• Consequence: WRAP53 NM_001143992.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 1.81
• Publications: 7 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyskeratosis congenita

  Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• telomere syndrome

  Inheritance: SD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0498 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000772 (116/150166) while in subpopulation AFR AF = 0.00101 (41/40576). AF 95% confidence interval is 0.000765. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRAP53	NM_001143992.2	MANE Select	c.1564dupG	p.Ala522GlyfsTer8	frameshift	Exon 11 of 11	NP_001137464.1	Q9BUR4
	WRAP53	NM_001143990.2		c.1564dupG	p.Ala522GlyfsTer8	frameshift	Exon 11 of 11	NP_001137462.1	Q9BUR4
	WRAP53	NM_001143991.2		c.1564dupG	p.Ala522GlyfsTer8	frameshift	Exon 11 of 11	NP_001137463.1	Q9BUR4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRAP53	ENST00000396463.7	TSL:1 MANE Select	c.1564dupG	p.Ala522GlyfsTer8	frameshift	Exon 11 of 11	ENSP00000379727.3	Q9BUR4
	WRAP53	ENST00000316024.9	TSL:1	c.1564dupG	p.Ala522GlyfsTer8	frameshift	Exon 10 of 10	ENSP00000324203.5	Q9BUR4
	WRAP53	ENST00000431639.6	TSL:1	c.1564dupG	p.Ala522GlyfsTer8	frameshift	Exon 11 of 11	ENSP00000397219.2	Q9BUR4

Frequencies

GnomAD3 genomes AF: 0.000773 AC: 116 AN: 150052 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000740

Gnomad OTH AF: 0.000974

GnomAD2 exomes AF: 0.00102 AC: 255 AN: 249660 AF XY: 0.000917

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.000927

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000894 AC: 1302 AN: 1455980 Hom.: 2 Cov.: 34 AF XY: 0.000900 AC XY: 652 AN XY: 724366

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000830 AC: 27 AN: 32524

American (AMR) AF: 0.000291 AC: 13 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26066

East Asian (EAS) AF: 0.000178 AC: 7 AN: 39368

South Asian (SAS) AF: 0.00105 AC: 90 AN: 85872

European-Finnish (FIN) AF: 0.00195 AC: 103 AN: 52898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.000916 AC: 1016 AN: 1108788

Other (OTH) AF: 0.000732 AC: 44 AN: 60114

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000772 AC: 116 AN: 150166 Hom.: 0 Cov.: 31 AF XY: 0.000791 AC XY: 58 AN XY: 73344

African (AFR) AF: 0.00101 AC: 41 AN: 40576

American (AMR) AF: 0.000132 AC: 2 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4706

European-Finnish (FIN) AF: 0.00193 AC: 20 AN: 10374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000740 AC: 50 AN: 67586

Other (OTH) AF: 0.000963 AC: 2 AN: 2076

Alfa AF: 0.000582 Hom.: 0

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	2	-	Dyskeratosis congenita, autosomal recessive 3 (2)
-	1	-	Dyskeratosis congenita (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=33/167	disease causing (ClinVar)

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: rs755116516; hg19: chr17-7606714; COSMIC: COSV56832994; COSMIC: COSV56832994;