rs149359927

Variant names:

• chr17-7702463-C-T
• rs149359927
• NM_001143992.2:c.1075C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001143992.2(WRAP53):​c.1075C>T​(p.Pro359Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,614,092 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (1 hom.)
• Consequence: WRAP53 NM_001143992.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.20
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01028204).
• BP6: Variant 17-7702463-C-T is Benign according to our data. Variant chr17-7702463-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 392640.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00086 (131/152314) while in subpopulation AFR AF = 0.00294 (122/41564). AF 95% confidence interval is 0.00251. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRAP53	NM_001143992.2	MANE Select	c.1075C>T	p.Pro359Ser	missense	Exon 8 of 11	NP_001137464.1	Q9BUR4
	WRAP53	NM_001143990.2		c.1075C>T	p.Pro359Ser	missense	Exon 8 of 11	NP_001137462.1	Q9BUR4
	WRAP53	NM_001143991.2		c.1075C>T	p.Pro359Ser	missense	Exon 8 of 11	NP_001137463.1	Q9BUR4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRAP53	ENST00000396463.7	TSL:1 MANE Select	c.1075C>T	p.Pro359Ser	missense	Exon 8 of 11	ENSP00000379727.3	Q9BUR4
	WRAP53	ENST00000316024.9	TSL:1	c.1075C>T	p.Pro359Ser	missense	Exon 7 of 10	ENSP00000324203.5	Q9BUR4
	WRAP53	ENST00000431639.6	TSL:1	c.1075C>T	p.Pro359Ser	missense	Exon 8 of 11	ENSP00000397219.2	Q9BUR4

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000151 AC: 38 AN: 250896 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00216

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000971 AC: 142 AN: 1461778 Hom.: 1 Cov.: 32 AF XY: 0.0000880 AC XY: 64 AN XY: 727200

African (AFR) AF: 0.00326 AC: 109 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.000364 AC: 22 AN: 60388

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74476

African (AFR) AF: 0.00294 AC: 122 AN: 41564

American (AMR) AF: 0.000327 AC: 5 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.000854

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Dyskeratosis congenita (1)
-	-	1	not specified (1)
-	-	1	WRAP53-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.93	T
PhyloP100		2.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.087
Sift	Benign	0.46	T
Sift4G	Benign	0.52	T
Polyphen		0.13	B
Vest4		0.39
MVP		0.25
MPC		0.42
ClinPred		0.011	T
GERP RS		2.5
Varity_R		0.062
gMVP		0.32
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs149359927; hg19: chr17-7605781;