17-7687471-G-A

Variant names:

• chr17-7687471-G-A
• rs2074027750
• NM_000546.6:c.-123C>T

Variant summary

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

The NM_000546.6(TP53):​c.-123C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000406 in 246,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TP53 NM_000546.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.381
• Publications: 0 publications found

Genes affected

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]

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=-0.78).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. 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
	TP53	NM_000546.6	MANE Select	c.-123C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_000537.3
	TP53	NM_000546.6	MANE Select	c.-123C>T		5_prime_UTR	Exon 1 of 11	NP_000537.3
	TP53	NM_001126112.3		c.-120C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001119584.1	K7PPA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.-123C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.-120C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.-357C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000406 AC: 1 AN: 246374 Hom.: 0 Cov.: 0 AF XY: 0.00000801 AC XY: 1 AN XY: 124844

African (AFR) AF: 0.00 AC: 0 AN: 7184

American (AMR) AF: 0.00 AC: 0 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9240

East Asian (EAS) AF: 0.00 AC: 0 AN: 22896

South Asian (SAS) AF: 0.00 AC: 0 AN: 3036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 158078

Other (OTH) AF: 0.0000611 AC: 1 AN: 16376

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Li-Fraumeni syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	16
DANN	Benign	0.85
PhyloP100		0.38
PromoterAI		0.0070	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: rs2074027750; hg19: chr17-7590789;