rs2287498

Variant names:

• chr17-7689242-C-A
• rs2287498
• NM_001143992.2:c.450C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-7689242-C-A
• chr17-7689242-C-G
• chr17-7689242-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001143992.2(WRAP53):​c.450C>A​(p.Phe150Leu) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F150F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: WRAP53 NM_001143992.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.513
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRAP53	NM_001143992.2	c.450C>A	p.Phe150Leu	missense_variant	Exon 3 of 11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2	c.450C>A	p.Phe150Leu	missense_variant	Exon 3 of 11		NP_001137462.1
WRAP53	NM_001143991.2	c.450C>A	p.Phe150Leu	missense_variant	Exon 3 of 11		NP_001137463.1
WRAP53	NM_018081.2	c.450C>A	p.Phe150Leu	missense_variant	Exon 2 of 10		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7	c.450C>A	p.Phe150Leu	missense_variant	Exon 3 of 11	1	NM_001143992.2	ENSP00000379727.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.0012	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.75	.;.;.;T
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-0.68	T
PhyloP100		-0.51
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.64
MutPred		0.55		Gain of disorder (P = 0.171);Gain of disorder (P = 0.171);Gain of disorder (P = 0.171);Gain of disorder (P = 0.171);
MVP		0.26
MPC		0.96
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.36
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2287498; hg19: chr17-7592560;