ENST00000316024:c.-1273C>G

Variant names:

• chr17-7687376-C-G
• ENST00000316024:c.-1273C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000316024(WRAP53):​c.-1273C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WRAP53 ENST00000316024 5_prime_UTR
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.25

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]

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7687376-C-G is Pathogenic according to our data. Variant chr17-7687376-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1524222.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.-29+1G>C		splice_donor_variant, intron_variant	Intron 1 of 10	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.-29+1G>C		splice_donor_variant, intron_variant	Intron 1 of 10	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 05, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-29+1G>C intronic variant is located in the 5' untranslated region (5’ UTR) of the TP53 gene. This intronic variant results from a G to C substitution one nucleotide after the first non-coding exon. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (Ambry internal data). Another variant impacting the same splice site, TP53 c.-29+1G>T, was identified in a family with Li Fraumeni Syndrome (Verselis SJ et al. Oncogene, 2000 Aug;19:4230-5). Further analyses of this variant did not detect any abnormally spliced transcript; however only transcripts from one allele were observed, suggesting monoallelic expression of the TP53 transcript. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies did not detect abnormal splicing in the set of samples tested; however additional analyses indicated the presence of transcripts from only one allele, as described for TP53 c.-29+1G>T (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Li-Fraumeni syndrome Uncertain:1

Jul 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1524222). This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This variant occurs in a non-coding region of the TP53 gene. It does not change the encoded amino acid sequence of the TP53 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Uncertain	0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 1

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: chr17-7590694; COSMIC: COSV53123147; COSMIC: COSV53123147;