rs73248508

Variant names:

• chr17-7701770-C-T
• rs73248508
• NM_001143992.2:c.936C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001143992.2(WRAP53):​c.936C>T​(p.Cys312Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,613,614 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (13 hom.)
• Consequence: WRAP53 NM_001143992.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.07
• Publications: 1 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 17-7701770-C-T is Benign according to our data. Variant chr17-7701770-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 325659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00524 (798/152338) while in subpopulation AFR AF = 0.0143 (596/41588). AF 95% confidence interval is 0.0134. There are 2 homozygotes in GnomAd4. There are 373 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.936C>T	p.Cys312Cys	synonymous	Exon 7 of 11	NP_001137464.1	Q9BUR4
	WRAP53	NM_001143990.2		c.936C>T	p.Cys312Cys	synonymous	Exon 7 of 11	NP_001137462.1	Q9BUR4
	WRAP53	NM_001143991.2		c.936C>T	p.Cys312Cys	synonymous	Exon 7 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.936C>T	p.Cys312Cys	synonymous	Exon 7 of 11	ENSP00000379727.3	Q9BUR4
	WRAP53	ENST00000316024.9	TSL:1	c.936C>T	p.Cys312Cys	synonymous	Exon 6 of 10	ENSP00000324203.5	Q9BUR4
	WRAP53	ENST00000431639.6	TSL:1	c.936C>T	p.Cys312Cys	synonymous	Exon 7 of 11	ENSP00000397219.2	Q9BUR4

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 796 AN: 152220 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00207 AC: 516 AN: 248954 AF XY: 0.00176

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000842

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000420

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00240 AC: 3507 AN: 1461276 Hom.: 13 Cov.: 32 AF XY: 0.00228 AC XY: 1658 AN XY: 726950

African (AFR) AF: 0.0161 AC: 540 AN: 33476

American (AMR) AF: 0.00116 AC: 52 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000569 AC: 49 AN: 86190

European-Finnish (FIN) AF: 0.000508 AC: 27 AN: 53130

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.00239 AC: 2659 AN: 1111894

Other (OTH) AF: 0.00285 AC: 172 AN: 60322

GnomAD4 genome AF: 0.00524 AC: 798 AN: 152338 Hom.: 2 Cov.: 32 AF XY: 0.00501 AC XY: 373 AN XY: 74476

African (AFR) AF: 0.0143 AC: 596 AN: 41588

American (AMR) AF: 0.00274 AC: 42 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00216 AC: 147 AN: 68042

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00347 Hom.: 1

Bravo AF: 0.00578

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00184

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	1.5
DANN	Benign	0.85
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73248508; hg19: chr17-7605088; COSMIC: COSV56833082; COSMIC: COSV56833082;