rs12951053

Positions:

• chr17-7674089-A-C

Variant summary

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

The NM_000546.6(TP53):​c.782+92T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,004,186 control chromosomes in the GnomAD database, including 7,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1031 hom., cov: 30)
  • Exomes 𝑓: 0.10 (6080 hom.)
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.64

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 17-7674089-A-C is Benign according to our data. Variant chr17-7674089-A-C is described in ClinVar as [Benign]. Clinvar id is 1243959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7674089-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.782+92T>G		intron_variant		ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.782+92T>G		intron_variant		1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15795 AN: 151722 Hom.: 1034 Cov.: 30

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0710

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0516

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0802

Gnomad OTH AF: 0.0908

GnomAD4 exome AF: 0.101 AC: 86008 AN: 852346 Hom.: 6080 AF XY: 0.105 AC XY: 46657 AN XY: 445052

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.0692

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.0543

Gnomad4 NFE exome AF: 0.0776

Gnomad4 OTH exome AF: 0.0998

GnomAD4 genome AF: 0.104 AC: 15811 AN: 151840 Hom.: 1031 Cov.: 30 AF XY: 0.106 AC XY: 7848 AN XY: 74200

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.0710

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.0516

Gnomad4 NFE AF: 0.0802

Gnomad4 OTH AF: 0.0936

Alfa AF: 0.0914 Hom.: 453

Bravo AF: 0.108

Asia WGS AF: 0.238 AC: 826 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	-	- -

Li-Fraumeni syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.49
DANN	Benign	0.71

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: rs12951053; hg19: chr17-7577407; COSMIC: COSV52747988; COSMIC: COSV52747988;