rs34016213

Variant names:

• chr17-7703032-T-C
• rs34016213
• NM_001143992.2:c.1308T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018081.2(WRAP53):​c.1308T>C​(p.Ala436Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,004 control chromosomes in the GnomAD database, including 834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (431 hom., cov: 31)
  • Exomes 𝑓: 0.0089 (403 hom.)
• Consequence: WRAP53 NM_018081.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.27
• Publications: 5 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=-0.92).
• BP6: Variant 17-7703032-T-C is Benign according to our data. Variant chr17-7703032-T-C is described in ClinVar as Benign. ClinVar VariationId is 260996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018081.2. 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.1308T>C	p.Ala436Ala	synonymous	Exon 10 of 11	NP_001137464.1
	WRAP53	NM_001143990.2		c.1308T>C	p.Ala436Ala	synonymous	Exon 10 of 11	NP_001137462.1
	WRAP53	NM_001143991.2		c.1308T>C	p.Ala436Ala	synonymous	Exon 10 of 11	NP_001137463.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRAP53	ENST00000396463.7	TSL:1 MANE Select	c.1308T>C	p.Ala436Ala	synonymous	Exon 10 of 11	ENSP00000379727.3
	WRAP53	ENST00000316024.9	TSL:1	c.1308T>C	p.Ala436Ala	synonymous	Exon 9 of 10	ENSP00000324203.5
	WRAP53	ENST00000431639.6	TSL:1	c.1308T>C	p.Ala436Ala	synonymous	Exon 10 of 11	ENSP00000397219.2

Frequencies

GnomAD3 genomes AF: 0.0448 AC: 6807 AN: 152046 Hom.: 430 Cov.: 31

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00810

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0147 AC: 3702 AN: 251352 AF XY: 0.0117

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00510

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00885 AC: 12943 AN: 1461840 Hom.: 403 Cov.: 33 AF XY: 0.00827 AC XY: 6016 AN XY: 727212

African (AFR) AF: 0.145 AC: 4850 AN: 33480

American (AMR) AF: 0.0117 AC: 525 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00879 AC: 758 AN: 86258

European-Finnish (FIN) AF: 0.00157 AC: 84 AN: 53380

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5766

European-Non Finnish (NFE) AF: 0.00515 AC: 5731 AN: 1112002

Other (OTH) AF: 0.0141 AC: 853 AN: 60394

GnomAD4 genome AF: 0.0448 AC: 6824 AN: 152164 Hom.: 431 Cov.: 31 AF XY: 0.0434 AC XY: 3232 AN XY: 74406

African (AFR) AF: 0.143 AC: 5939 AN: 41480

American (AMR) AF: 0.0261 AC: 399 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00769 AC: 37 AN: 4812

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00529 AC: 360 AN: 68002

Other (OTH) AF: 0.0279 AC: 59 AN: 2112

Alfa AF: 0.0150 Hom.: 98

Bravo AF: 0.0512

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00610

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	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
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.11
DANN	Benign	0.35
PhyloP100		-2.3
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: rs34016213; hg19: chr17-7606350; COSMIC: COSV56834677; COSMIC: COSV56834677;