17-7688222-T-C

Variant names:

• chr17-7688222-T-C
• rs1421314
• ENST00000316024.9:c.-427T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000316024.9(WRAP53):​c.-427T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00651 in 194,222 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0081 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: WRAP53 ENST00000316024.9 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.791
• Publications: 2 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• dyskeratosis congenita

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-7688222-T-C is Benign according to our data. Variant chr17-7688222-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1193678.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00809 (1231/152252) while in subpopulation AFR AF = 0.0283 (1174/41548). AF 95% confidence interval is 0.0269. There are 21 homozygotes in GnomAd4. There are 540 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRAP53	NM_001143990.2	c.-1-426T>C		intron_variant	Intron 1 of 10		NP_001137462.1
WRAP53	NM_001143991.2	c.-1-426T>C		intron_variant	Intron 1 of 10		NP_001137463.1
WRAP53	NM_018081.2	c.-427T>C		upstream_gene_variant			NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000316024.9	c.-427T>C		5_prime_UTR_variant	Exon 1 of 10	1		ENSP00000324203.5
WRAP53	ENST00000431639.6	c.-1-426T>C		intron_variant	Intron 1 of 10	1		ENSP00000397219.2
WRAP53	ENST00000457584.6	c.-1-426T>C		intron_variant	Intron 1 of 10	1		ENSP00000411061.2

Frequencies

GnomAD3 genomes AF: 0.00809 AC: 1231 AN: 152134 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

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: 0.000103

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000786 AC: 33 AN: 41970 Hom.: 0 Cov.: 0 AF XY: 0.000766 AC XY: 17 AN XY: 22184

African (AFR) AF: 0.0292 AC: 22 AN: 754

American (AMR) AF: 0.00143 AC: 5 AN: 3486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 816

East Asian (EAS) AF: 0.00 AC: 0 AN: 1814

South Asian (SAS) AF: 0.000295 AC: 2 AN: 6788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 118

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 24324

Other (OTH) AF: 0.00181 AC: 4 AN: 2210

GnomAD4 genome AF: 0.00809 AC: 1231 AN: 152252 Hom.: 21 Cov.: 32 AF XY: 0.00725 AC XY: 540 AN XY: 74448

African (AFR) AF: 0.0283 AC: 1174 AN: 41548

American (AMR) AF: 0.00288 AC: 44 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68000

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00396 Hom.: 1

Bravo AF: 0.00897

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 04, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.48
PhyloP100		-0.79
PromoterAI		-0.018	Neutral
Mutation Taster		=300/0	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: rs1421314; hg19: chr17-7591540;