Variant chr17-7689284-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_001143992.2(WRAP53):c.492C>A(p.Phe164Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

WRAP53
NM_001143992.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: -0.168

Variant links:

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 links:

WRAP53 (HGNC:):

WRAP53 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-7689284-C-A is Pathogenic according to our data. Variant chr17-7689284-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 41252.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7689284-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRAP53	NM_001143992.2 linkuse as main transcript	c.492C>A	p.Phe164Leu	missense_variant	3/11	ENST00000396463.7	NP_001137464.1	Q9BUR4
WRAP53	NM_001143990.2 linkuse as main transcript	c.492C>A	p.Phe164Leu	missense_variant	3/11		NP_001137462.1	Q9BUR4
WRAP53	NM_001143991.2 linkuse as main transcript	c.492C>A	p.Phe164Leu	missense_variant	3/11		NP_001137463.1	Q9BUR4
WRAP53	NM_018081.2 linkuse as main transcript	c.492C>A	p.Phe164Leu	missense_variant	2/10		NP_060551.2	Q9BUR4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7 linkuse as main transcript	c.492C>A	p.Phe164Leu	missense_variant	3/11	1	NM_001143992.2	ENSP00000379727.3		Q9BUR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal recessive 3

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21205863) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T;T;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.85

.;.;.;D

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.1

D;D;D;D

REVEL

Benign

0.25

Sift

Benign

0.036

D;D;D;D

Sift4G

Benign

0.076

T;T;T;T

Polyphen

0.79

P;P;P;P

Vest4

0.80

MutPred

0.28

Gain of disorder (P = 0.1668);Gain of disorder (P = 0.1668);Gain of disorder (P = 0.1668);Gain of disorder (P = 0.1668);

MVP

0.80

MPC

0.59

ClinPred

0.98

GERP RS

-1.0

Varity_R

0.25

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over