rs2287499

Variant names:

• chr17-7688850-C-G
• rs2287499
• NM_001143992.2:c.202C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-7688850-C-G
• chr17-7688850-C-T

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.202C>G​(p.Arg68Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,614,002 control chromosomes in the GnomAD database, including 38,182 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R68P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (13477 hom., cov: 32)
  • Exomes 𝑓: 0.14 (24705 hom.)
• Consequence: WRAP53 NM_001143992.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.419
• Publications: 81 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=9.1231465E-7).
• BP6: Variant 17-7688850-C-G is Benign according to our data. Variant chr17-7688850-C-G is described in ClinVar as Benign. ClinVar VariationId is 261001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.75 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.202C>G	p.Arg68Gly	missense	Exon 2 of 11	NP_001137464.1	Q9BUR4
	WRAP53	NM_001143990.2		c.202C>G	p.Arg68Gly	missense	Exon 2 of 11	NP_001137462.1	Q9BUR4
	WRAP53	NM_001143991.2		c.202C>G	p.Arg68Gly	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.202C>G	p.Arg68Gly	missense	Exon 2 of 11	ENSP00000379727.3	Q9BUR4
	WRAP53	ENST00000316024.9	TSL:1	c.202C>G	p.Arg68Gly	missense	Exon 1 of 10	ENSP00000324203.5	Q9BUR4
	WRAP53	ENST00000431639.6	TSL:1	c.202C>G	p.Arg68Gly	missense	Exon 2 of 11	ENSP00000397219.2	Q9BUR4

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47352 AN: 151998 Hom.: 13437 Cov.: 32

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.0622

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.266

GnomAD2 exomes AF: 0.199 AC: 50003 AN: 250972 AF XY: 0.190

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.309

Gnomad FIN exome AF: 0.0609

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.144 AC: 211092 AN: 1461884 Hom.: 24705 Cov.: 33 AF XY: 0.146 AC XY: 106161 AN XY: 727244

African (AFR) AF: 0.783 AC: 26218 AN: 33480

American (AMR) AF: 0.205 AC: 9173 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2899 AN: 26136

East Asian (EAS) AF: 0.285 AC: 11308 AN: 39700

South Asian (SAS) AF: 0.260 AC: 22470 AN: 86258

European-Finnish (FIN) AF: 0.0643 AC: 3434 AN: 53412

Middle Eastern (MID) AF: 0.182 AC: 1049 AN: 5768

European-Non Finnish (NFE) AF: 0.111 AC: 123787 AN: 1112010

Other (OTH) AF: 0.178 AC: 10754 AN: 60396

GnomAD4 genome AF: 0.312 AC: 47448 AN: 152118 Hom.: 13477 Cov.: 32 AF XY: 0.306 AC XY: 22739 AN XY: 74370

African (AFR) AF: 0.758 AC: 31420 AN: 41478

American (AMR) AF: 0.228 AC: 3479 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 393 AN: 3472

East Asian (EAS) AF: 0.307 AC: 1587 AN: 5168

South Asian (SAS) AF: 0.252 AC: 1218 AN: 4824

European-Finnish (FIN) AF: 0.0622 AC: 659 AN: 10600

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8010 AN: 67984

Other (OTH) AF: 0.267 AC: 562 AN: 2108

Alfa AF: 0.124 Hom.: 1272

Bravo AF: 0.341

TwinsUK AF: 0.110 AC: 408

ALSPAC AF: 0.116 AC: 446

ESP6500AA AF: 0.741 AC: 3265

ESP6500EA AF: 0.116 AC: 998

ExAC AF: 0.212 AC: 25704

Asia WGS AF: 0.303 AC: 1051 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.9
DANN	Benign	0.61
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	9.1e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.42
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.041
Sift	Benign	0.80	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.059
MPC		0.31
ClinPred		0.0018	T
GERP RS		1.1
PromoterAI		0.0042	Neutral
Varity_R		0.040
gMVP		0.11
Mutation Taster		=99/1	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: rs2287499; hg19: chr17-7592168; COSMIC: COSV52834815; COSMIC: COSV52834815;