17-7688850-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001143992.2(WRAP53):​c.202C>T​(p.Arg68Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R68G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WRAP53 NM_001143992.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• dyskeratosis congenita

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05171126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRAP53	NM_001143992.2	c.202C>T	p.Arg68Trp	missense_variant	Exon 2 of 11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2	c.202C>T	p.Arg68Trp	missense_variant	Exon 2 of 11		NP_001137462.1
WRAP53	NM_001143991.2	c.202C>T	p.Arg68Trp	missense_variant	Exon 2 of 11		NP_001137463.1
WRAP53	NM_018081.2	c.202C>T	p.Arg68Trp	missense_variant	Exon 1 of 10		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7	c.202C>T	p.Arg68Trp	missense_variant	Exon 2 of 11	1	NM_001143992.2	ENSP00000379727.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1272

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0099	T;T;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.25	.;.;.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.052	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		0.42
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.67	N;N;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.17	T;T;T;T;D
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.14
MutPred		0.18		Gain of catalytic residue at E66 (P = 0.248);Gain of catalytic residue at E66 (P = 0.248);Gain of catalytic residue at E66 (P = 0.248);Gain of catalytic residue at E66 (P = 0.248);Gain of catalytic residue at E66 (P = 0.248);
MVP		0.043
MPC		0.39
ClinPred		0.12	T
GERP RS		1.1
PromoterAI		-0.0033	Neutral
Varity_R		0.036
gMVP		0.11

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;