rs281865547

Positions:

• chr17-7689284-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: -0.168

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 (HGNC:):

ACMG classification

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	c.492C>A	p.Phe164Leu	missense_variant	3/11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2	c.492C>A	p.Phe164Leu	missense_variant	3/11		NP_001137462.1
WRAP53	NM_001143991.2	c.492C>A	p.Phe164Leu	missense_variant	3/11		NP_001137463.1
WRAP53	NM_018081.2	c.492C>A	p.Phe164Leu	missense_variant	2/10		NP_060551.2

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727242

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.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita, autosomal recessive 3 Pathogenic:1 Other: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	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
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	D
LIST_S2	Benign	0.85	.;.;.;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.66	T
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	D
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

Other links and lift over

dbSNP: rs281865547; hg19: chr17-7592602;