17-7689284-C-G

Variant names:

• chr17-7689284-C-G
• NM_001143992.2:c.492C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1 PM2

The NM_001143992.2(WRAP53):​c.492C>G​(p.Phe164Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WRAP53 NM_001143992.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_001143992.2 (WRAP53) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRAP53	NM_001143992.2	c.492C>G	p.Phe164Leu	missense_variant	Exon 3 of 11	ENST00000396463.7	NP_001137464.1
WRAP53	NM_001143990.2	c.492C>G	p.Phe164Leu	missense_variant	Exon 3 of 11		NP_001137462.1
WRAP53	NM_001143991.2	c.492C>G	p.Phe164Leu	missense_variant	Exon 3 of 11		NP_001137463.1
WRAP53	NM_018081.2	c.492C>G	p.Phe164Leu	missense_variant	Exon 2 of 10		NP_060551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRAP53	ENST00000396463.7	c.492C>G	p.Phe164Leu	missense_variant	Exon 3 of 11	1	NM_001143992.2	ENSP00000379727.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	.;.;.;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Benign	-0.93	T
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.25
Sift	Benign	0.036	D;D;D;D
Sift4G	Benign	0.076	T;T;T;T
Polyphen		0.79	P;P;P;P
Vest4		0.80
MutPred		0.28		Gain of disorder (P = 0.1668);Gain of disorder (P = 0.1668);Gain of disorder (P = 0.1668);Gain of disorder (P = 0.1668);
MVP		0.80
MPC		0.59
ClinPred		0.98	D
GERP RS		-1.0
Varity_R		0.25
gMVP		0.50

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7592602;