rs4968187

Positions:

• chr17-7669124-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.*485G>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 0.0214 in 297,812 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (172 hom., cov: 32)
  • Exomes 𝑓: 0.023 (202 hom.)
• Consequence: TP53 ENST00000269305.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0280

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=-0.88).
• BP6: Variant 17-7669124-C-T is Benign according to our data. Variant chr17-7669124-C-T is described in ClinVar as [Benign]. Clinvar id is 325637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.*485G>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.*485G>A		3_prime_UTR_variant	11/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3030 AN: 152070 Hom.: 172 Cov.: 32

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.0260

GnomAD4 exome AF: 0.0230 AC: 3348 AN: 145624 Hom.: 202 Cov.: 0 AF XY: 0.0215 AC XY: 1534 AN XY: 71256

Gnomad4 AFR exome AF: 0.00446

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.00634

Gnomad4 FIN exome AF: 0.0278

Gnomad4 NFE exome AF: 0.00241

Gnomad4 OTH exome AF: 0.0175

GnomAD4 genome AF: 0.0199 AC: 3036 AN: 152188 Hom.: 172 Cov.: 32 AF XY: 0.0234 AC XY: 1738 AN XY: 74404

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.100

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.0252

Alfa AF: 0.0128 Hom.: 170

Bravo AF: 0.0277

Asia WGS AF: 0.0660 AC: 227 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	Genome-Nilou Lab	Jun 18, 2022	- -
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. -

not provided Benign:2

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

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	-0.88
CADD	Benign	3.9
DANN	Benign	0.58

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: rs4968187; hg19: chr17-7572442;