17-7668783-C-T

Position:

• chr17-7668783-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000269305.9(TP53):​c.*826G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0505 in 223,876 control chromosomes in the GnomAD database, including 368 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (268 hom., cov: 30)
  • Exomes 𝑓: 0.048 (100 hom.)
• Consequence: TP53 ENST00000269305.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.390

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-7668783-C-T is Benign according to our data. Variant chr17-7668783-C-T is described in ClinVar as [Benign]. Clinvar id is 325623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.*826G>A		3_prime_UTR_variant	11/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.*826G>A		3_prime_UTR_variant	11/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes AF: 0.0516 AC: 7572 AN: 146758 Hom.: 264 Cov.: 30

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.0500

Gnomad EAS AF: 0.0713

Gnomad SAS AF: 0.0749

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.00667

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0420

GnomAD4 exome AF: 0.0479 AC: 3692 AN: 77010 Hom.: 100 Cov.: 0 AF XY: 0.0484 AC XY: 1724 AN XY: 35588

Gnomad4 AFR exome AF: 0.0274

Gnomad4 AMR exome AF: 0.0374

Gnomad4 ASJ exome AF: 0.0478

Gnomad4 EAS exome AF: 0.0599

Gnomad4 SAS exome AF: 0.0912

Gnomad4 FIN exome AF: 0.0357

Gnomad4 NFE exome AF: 0.0471

Gnomad4 OTH exome AF: 0.0476

GnomAD4 genome AF: 0.0518 AC: 7603 AN: 146866 Hom.: 268 Cov.: 30 AF XY: 0.0546 AC XY: 3883 AN XY: 71146

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.0455

Gnomad4 ASJ AF: 0.0500

Gnomad4 EAS AF: 0.0719

Gnomad4 SAS AF: 0.0753

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0541

Gnomad4 OTH AF: 0.0495

Alfa AF: 0.0555 Hom.: 34

Bravo AF: 0.0456

Asia WGS AF: 0.126 AC: 436 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs17884306; hg19: chr17-7572101;