Genetic Variant WRAP53:p.Gly435Arg (chr17-7703027-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001143992.2(WRAP53):c.1303G>C(p.Gly435Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

WRAP53
NM_001143992.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.84

Publications

0 publications found

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 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

WRAP53 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
WRAP53	NM_001143992.2 link	c.1303G>C	p.Gly435Arg	missense_variant	Exon 10 of 11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2 link	c.1303G>C	p.Gly435Arg	missense_variant	Exon 10 of 11		NP_001137462.1
WRAP53	NM_001143991.2 link	c.1303G>C	p.Gly435Arg	missense_variant	Exon 10 of 11		NP_001137463.1
WRAP53	NM_018081.2 link	c.1303G>C	p.Gly435Arg	missense_variant	Exon 9 of 10		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7 link	c.1303G>C	p.Gly435Arg	missense_variant	Exon 10 of 11	1	NM_001143992.2	ENSP00000379727.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T;T;T;T

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;.;.;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.38

PhyloP100

7.8

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.5

D;D;D;D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.026

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.94

MutPred

0.78

Loss of glycosylation at S434 (P = 0.0657);Loss of glycosylation at S434 (P = 0.0657);Loss of glycosylation at S434 (P = 0.0657);Loss of glycosylation at S434 (P = 0.0657);.;

MVP

0.75

MPC

0.97

ClinPred

0.99

GERP RS

5.8

Varity_R

0.62

gMVP

0.75

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over