Genetic Variant WRAP53:p.Phe150Leu (chr17-7689242-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.513

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
dyskeratosis congenita
Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
telomere syndrome
Inheritance: SD Classification: MODERATE Submitted by: ClinGen

WRAP53 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143992.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WRAP53	NM_001143992.2	MANE Select	c.450C>A	p.Phe150Leu	missense	Exon 3 of 11	NP_001137464.1	Q9BUR4
WRAP53	NM_001143990.2		c.450C>A	p.Phe150Leu	missense	Exon 3 of 11	NP_001137462.1	Q9BUR4
WRAP53	NM_001143991.2		c.450C>A	p.Phe150Leu	missense	Exon 3 of 11	NP_001137463.1	Q9BUR4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WRAP53	ENST00000396463.7	TSL:1 MANE Select	c.450C>A	p.Phe150Leu	missense	Exon 3 of 11	ENSP00000379727.3	Q9BUR4
WRAP53	ENST00000316024.9	TSL:1	c.450C>A	p.Phe150Leu	missense	Exon 2 of 10	ENSP00000324203.5	Q9BUR4
WRAP53	ENST00000431639.6	TSL:1	c.450C>A	p.Phe150Leu	missense	Exon 3 of 11	ENSP00000397219.2	Q9BUR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.0012

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.75

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.68

PhyloP100

-0.51

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.31

Sift

Uncertain

0.010

Sift4G

Uncertain

0.031

Polyphen

1.0

Vest4

0.64

MutPred

0.55

Gain of disorder (P = 0.171)

MVP

0.26

MPC

0.96

ClinPred

0.97

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over