17-7703404-C-G

Variant names:

• chr17-7703404-C-G
• rs7640
• NM_001143992.2:c.1565C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001143992.2(WRAP53):​c.1565C>G​(p.Ala522Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,613,258 control chromosomes in the GnomAD database, including 69,315 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A522R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (17179 hom., cov: 30)
  • Exomes 𝑓: 0.24 (52136 hom.)
• Consequence: WRAP53 NM_001143992.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.39
• Publications: 39 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.1508036E-7).
• BP6: Variant 17-7703404-C-G is Benign according to our data. Variant chr17-7703404-C-G is described in ClinVar as Benign. ClinVar VariationId is 260999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

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.1565C>G	p.Ala522Gly	missense	Exon 11 of 11	NP_001137464.1	Q9BUR4
	WRAP53	NM_001143990.2		c.1565C>G	p.Ala522Gly	missense	Exon 11 of 11	NP_001137462.1	Q9BUR4
	WRAP53	NM_001143991.2		c.1565C>G	p.Ala522Gly	missense	Exon 11 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.1565C>G	p.Ala522Gly	missense	Exon 11 of 11	ENSP00000379727.3	Q9BUR4
	WRAP53	ENST00000316024.9	TSL:1	c.1565C>G	p.Ala522Gly	missense	Exon 10 of 10	ENSP00000324203.5	Q9BUR4
	WRAP53	ENST00000431639.6	TSL:1	c.1565C>G	p.Ala522Gly	missense	Exon 11 of 11	ENSP00000397219.2	Q9BUR4

Frequencies

GnomAD3 genomes AF: 0.396 AC: 59935 AN: 151452 Hom.: 17124 Cov.: 30

Gnomad AFR AF: 0.811

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.336

GnomAD2 exomes AF: 0.299 AC: 75127 AN: 250874 AF XY: 0.294

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.266

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.421

Gnomad FIN exome AF: 0.206

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.241 AC: 352359 AN: 1461688 Hom.: 52136 Cov.: 46 AF XY: 0.245 AC XY: 178100 AN XY: 727146

African (AFR) AF: 0.835 AC: 27955 AN: 33466

American (AMR) AF: 0.268 AC: 11993 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5089 AN: 26134

East Asian (EAS) AF: 0.394 AC: 15643 AN: 39694

South Asian (SAS) AF: 0.435 AC: 37541 AN: 86246

European-Finnish (FIN) AF: 0.209 AC: 11135 AN: 53398

Middle Eastern (MID) AF: 0.238 AC: 1370 AN: 5768

European-Non Finnish (NFE) AF: 0.203 AC: 225321 AN: 1111884

Other (OTH) AF: 0.270 AC: 16312 AN: 60386

GnomAD4 genome AF: 0.396 AC: 60067 AN: 151570 Hom.: 17179 Cov.: 30 AF XY: 0.394 AC XY: 29176 AN XY: 74040

African (AFR) AF: 0.812 AC: 33484 AN: 41258

American (AMR) AF: 0.283 AC: 4305 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 682 AN: 3466

East Asian (EAS) AF: 0.428 AC: 2193 AN: 5120

South Asian (SAS) AF: 0.434 AC: 2071 AN: 4772

European-Finnish (FIN) AF: 0.211 AC: 2217 AN: 10514

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14125 AN: 67904

Other (OTH) AF: 0.341 AC: 716 AN: 2098

Alfa AF: 0.212 Hom.: 2564

Bravo AF: 0.417

TwinsUK AF: 0.199 AC: 738

ALSPAC AF: 0.203 AC: 781

ESP6500AA AF: 0.788 AC: 3470

ESP6500EA AF: 0.195 AC: 1675

ExAC AF: 0.313 AC: 37967

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Dyskeratosis congenita, autosomal recessive 3 (2)
-	-	1	Dyskeratosis congenita (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.0090
DANN	Benign	0.62
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00050	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-0.99	T
PhyloP100		-1.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.024
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.016
MPC		0.24
ClinPred		0.0045	T
GERP RS		-6.6
Varity_R		0.017
gMVP		0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs7640; hg19: chr17-7606722; COSMIC: COSV56832921; COSMIC: COSV56832921;