rs116535684

chr17-7702801-G-Achr17-7702801-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001143992.2(WRAP53):c.1223G>A(p.Gly408Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000946 in 1,613,998 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0049 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: WRAP53 NM_001143992.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.520

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008924812).
• BP6: Variant 17-7702801-G-A is Benign according to our data. Variant chr17-7702801-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260995.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=1}. Variant chr17-7702801-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00492 (749/152262) while in subpopulation AFR AF= 0.0169 (700/41532). AF 95% confidence interval is 0.0158. There are 8 homozygotes in gnomad4. There are 369 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRAP53	NM_001143992.2	c.1223G>A	p.Gly408Asp	missense_variant	9/11	ENST00000396463.7
WRAP53	NM_001143990.2	c.1223G>A	p.Gly408Asp	missense_variant	9/11
WRAP53	NM_001143991.2	c.1223G>A	p.Gly408Asp	missense_variant	9/11
WRAP53	NM_018081.2	c.1223G>A	p.Gly408Asp	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRAP53	ENST00000396463.7	c.1223G>A	p.Gly408Asp	missense_variant	9/11	1	NM_001143992.2	P1

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 746 AN: 152144 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00143 AC: 359 AN: 251204 Hom.: 2 AF XY: 0.00101 AC XY: 137 AN XY: 135774

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000532 AC: 778 AN: 1461736 Hom.: 1 Cov.: 33 AF XY: 0.000433 AC XY: 315 AN XY: 727178

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00492 AC: 749 AN: 152262 Hom.: 8 Cov.: 31 AF XY: 0.00496 AC XY: 369 AN XY: 74442

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000630 Hom.: 1

Bravo AF: 0.00588

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00180 AC: 218

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 20, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	16
Dann	Benign	0.55
DEOGEN2	Benign	0.0092	T;T;T;T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.35	N
MetaRNN	Benign	0.0089	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.30	N;N;N;N;N
REVEL	Benign	0.051
Sift	Benign	0.62	T;T;T;T;T
Sift4G	Benign	0.63	T;T;T;T;T
Polyphen		0.0030	B;B;B;B;B
Vest4		0.22
MVP		0.093
MPC		0.31
ClinPred		0.00047	T
GERP RS		-0.75
Varity_R		0.039
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs116535684; hg19: chr17-7606119;