17-7688501-C-A

Variant names:

• chr17-7688501-C-A
• rs748265946
• NM_001143992.2:c.-62C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001143992.2(WRAP53):​c.-62C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 655,676 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: WRAP53 NM_001143992.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.390
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).

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.-62C>A		5_prime_UTR	Exon 1 of 11	NP_001137464.1	Q9BUR4
	WRAP53	NM_018081.2		c.-148C>A		5_prime_UTR	Exon 1 of 10	NP_060551.2	Q9BUR4
	WRAP53	NM_001143990.2		c.-1-147C>A		intron	N/A	NP_001137462.1	Q9BUR4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRAP53	ENST00000396463.7	TSL:1 MANE Select	c.-62C>A		5_prime_UTR	Exon 1 of 11	ENSP00000379727.3	Q9BUR4
	WRAP53	ENST00000316024.9	TSL:1	c.-148C>A		5_prime_UTR	Exon 1 of 10	ENSP00000324203.5	Q9BUR4
	WRAP53	ENST00000534050.5	TSL:1	c.-148C>A		5_prime_UTR	Exon 1 of 9	ENSP00000434999.1	E9PMG4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000153 AC: 1 AN: 655676 Hom.: 0 Cov.: 9 AF XY: 0.00000295 AC XY: 1 AN XY: 338608

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16214

American (AMR) AF: 0.00 AC: 0 AN: 22056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15690

East Asian (EAS) AF: 0.00 AC: 0 AN: 32254

South Asian (SAS) AF: 0.00 AC: 0 AN: 52140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2456

European-Non Finnish (NFE) AF: 0.00000222 AC: 1 AN: 450464

Other (OTH) AF: 0.00 AC: 0 AN: 32868

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.4
DANN	Benign	0.63
PhyloP100		-0.39
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs748265946; hg19: chr17-7591819;