NM_001143992.2:c.1019A>G

Variant names:

• chr17-7702407-A-G
• rs1555530889
• NM_001143992.2:c.1019A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001143992.2(WRAP53):​c.1019A>G​(p.Tyr340Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y340Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WRAP53 NM_001143992.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRAP53	NM_001143992.2	MANE Select	c.1019A>G	p.Tyr340Cys	missense	Exon 8 of 11	NP_001137464.1
	WRAP53	NM_001143990.2		c.1019A>G	p.Tyr340Cys	missense	Exon 8 of 11	NP_001137462.1
	WRAP53	NM_001143991.2		c.1019A>G	p.Tyr340Cys	missense	Exon 8 of 11	NP_001137463.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRAP53	ENST00000396463.7	TSL:1 MANE Select	c.1019A>G	p.Tyr340Cys	missense	Exon 8 of 11	ENSP00000379727.3
	WRAP53	ENST00000316024.9	TSL:1	c.1019A>G	p.Tyr340Cys	missense	Exon 7 of 10	ENSP00000324203.5
	WRAP53	ENST00000431639.6	TSL:1	c.1019A>G	p.Tyr340Cys	missense	Exon 8 of 11	ENSP00000397219.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.14	T
PhyloP100		4.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.51		Gain of catalytic residue at Y340 (P = 0.087)
MVP		0.51
MPC		0.98
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.39
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555530889; hg19: chr17-7605725;