rs7640

Positions:

• chr17-7703404-C-A
• chr17-7703404-C-G
• chr17-7703404-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001143992.2(WRAP53):​c.1565C>A​(p.Ala522Glu) 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. 14/20 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. A522G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: WRAP53 NM_001143992.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05547273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRAP53	NM_001143992.2	c.1565C>A	p.Ala522Glu	missense_variant	11/11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2	c.1565C>A	p.Ala522Glu	missense_variant	11/11		NP_001137462.1
WRAP53	NM_001143991.2	c.1565C>A	p.Ala522Glu	missense_variant	11/11		NP_001137463.1
WRAP53	NM_018081.2	c.1565C>A	p.Ala522Glu	missense_variant	10/10		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7	c.1565C>A	p.Ala522Glu	missense_variant	11/11	1	NM_001143992.2	ENSP00000379727	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.028
DANN	Benign	0.84
DEOGEN2	Benign	0.0083	T;T;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.31	.;.;.;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.055	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.18	N;N;N;N;N
REVEL	Benign	0.026
Sift	Uncertain	0.016	D;D;D;D;D
Sift4G	Benign	0.085	T;T;T;T;T
Polyphen		0.0060	B;B;B;B;B
Vest4		0.15
MutPred		0.41		Gain of disorder (P = 0.0089);Gain of disorder (P = 0.0089);Gain of disorder (P = 0.0089);Gain of disorder (P = 0.0089);.;
MVP		0.14
MPC		0.29
ClinPred		0.13	T
GERP RS		-6.6
Varity_R		0.039
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs7640; hg19: chr17-7606722;