rs17880282

Variant names:

• chr17-7688679-C-T
• rs17880282
• NM_001143992.2:c.31C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7688679-C-T
• chr17-7688679-C-G

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.31C>T​(p.Pro11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,614,206 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (128 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (107 hom.)
• Consequence: WRAP53 NM_001143992.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0590
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015588999).
• BP6: Variant 17-7688679-C-T is Benign according to our data. Variant chr17-7688679-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 325650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0755 is higher than 0.05.

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.31C>T	p.Pro11Ser	missense	Exon 2 of 11	NP_001137464.1	Q9BUR4
	WRAP53	NM_001143990.2		c.31C>T	p.Pro11Ser	missense	Exon 2 of 11	NP_001137462.1	Q9BUR4
	WRAP53	NM_001143991.2		c.31C>T	p.Pro11Ser	missense	Exon 2 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.31C>T	p.Pro11Ser	missense	Exon 2 of 11	ENSP00000379727.3	Q9BUR4
	WRAP53	ENST00000316024.9	TSL:1	c.31C>T	p.Pro11Ser	missense	Exon 1 of 10	ENSP00000324203.5	Q9BUR4
	WRAP53	ENST00000431639.6	TSL:1	c.31C>T	p.Pro11Ser	missense	Exon 2 of 11	ENSP00000397219.2	Q9BUR4

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3509 AN: 152198 Hom.: 129 Cov.: 32

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.00626 AC: 1573 AN: 251400 AF XY: 0.00456

Gnomad AFR exome AF: 0.0810

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00257 AC: 3750 AN: 1461890 Hom.: 107 Cov.: 31 AF XY: 0.00222 AC XY: 1618 AN XY: 727248

African (AFR) AF: 0.0790 AC: 2644 AN: 33480

American (AMR) AF: 0.00499 AC: 223 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.000381 AC: 424 AN: 1112012

Other (OTH) AF: 0.00594 AC: 359 AN: 60396

GnomAD4 genome AF: 0.0230 AC: 3509 AN: 152316 Hom.: 128 Cov.: 32 AF XY: 0.0218 AC XY: 1626 AN XY: 74474

African (AFR) AF: 0.0777 AC: 3230 AN: 41548

American (AMR) AF: 0.0122 AC: 186 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68034

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.00836 Hom.: 129

Bravo AF: 0.0270

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0794 AC: 350

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00755 AC: 917

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Dyskeratosis congenita, autosomal recessive 3 (2)
-	-	1	Dyskeratosis congenita (1)
-	-	1	Dyskeratosis Congenita, Recessive (1)
-	-	1	Li-Fraumeni syndrome (1)
-	-	1	WRAP53-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.059
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.063
Sift	Uncertain	0.023	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.011	B
Vest4		0.11
MVP		0.068
MPC		0.25
ClinPred		0.021	T
GERP RS		0.97
PromoterAI		-0.012	Neutral
Varity_R		0.076
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs17880282; hg19: chr17-7591997;