17-7703480-G-C

Variant names:

• chr17-7703480-G-C
• rs146994329
• NM_001143992.2:c.1641G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001143992.2(WRAP53):​c.1641G>C​(p.Leu547Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L547L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WRAP53 NM_001143992.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP7: Synonymous conserved (PhyloP=-0.237 with no splicing effect.

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.1641G>C	p.Leu547Leu	synonymous	Exon 11 of 11	NP_001137464.1	Q9BUR4
	WRAP53	NM_001143990.2		c.1641G>C	p.Leu547Leu	synonymous	Exon 11 of 11	NP_001137462.1	Q9BUR4
	WRAP53	NM_001143991.2		c.1641G>C	p.Leu547Leu	synonymous	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.1641G>C	p.Leu547Leu	synonymous	Exon 11 of 11	ENSP00000379727.3	Q9BUR4
	WRAP53	ENST00000316024.9	TSL:1	c.1641G>C	p.Leu547Leu	synonymous	Exon 10 of 10	ENSP00000324203.5	Q9BUR4
	WRAP53	ENST00000431639.6	TSL:1	c.1641G>C	p.Leu547Leu	synonymous	Exon 11 of 11	ENSP00000397219.2	Q9BUR4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250732 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457154 Hom.: 0 Cov.: 40 AF XY: 0.00000138 AC XY: 1 AN XY: 724990

African (AFR) AF: 0.00 AC: 0 AN: 33058

American (AMR) AF: 0.00 AC: 0 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 38946

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109738

Other (OTH) AF: 0.00 AC: 0 AN: 60076

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.64
DANN	Benign	0.56
PhyloP100		-0.24

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: rs146994329; hg19: chr17-7606798;