rs146994329

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-7703480-G-C
• chr17-7703480-G-T

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• dyskeratosis congenita

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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRAP53	NM_001143992.2	c.1641G>C	p.Leu547Leu	synonymous_variant	Exon 11 of 11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2	c.1641G>C	p.Leu547Leu	synonymous_variant	Exon 11 of 11		NP_001137462.1
WRAP53	NM_001143991.2	c.1641G>C	p.Leu547Leu	synonymous_variant	Exon 11 of 11		NP_001137463.1
WRAP53	NM_018081.2	c.1641G>C	p.Leu547Leu	synonymous_variant	Exon 10 of 10		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7	c.1641G>C	p.Leu547Leu	synonymous_variant	Exon 11 of 11	1	NM_001143992.2	ENSP00000379727.3

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 v4.3

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;