rs9895829

Positions:

• chr17-7675361-A-G

Variant summary

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

The ENST00000504937.5(TP53):​c.-146T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,527,276 control chromosomes in the GnomAD database, including 3,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (500 hom., cov: 31)
  • Exomes 𝑓: 0.059 (2622 hom.)
• Consequence: TP53 ENST00000504937.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.545

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 17-7675361-A-G is Benign according to our data. Variant chr17-7675361-A-G is described in ClinVar as [Benign]. Clinvar id is 1245512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.376-125T>C		intron_variant		ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.376-125T>C		intron_variant		1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes AF: 0.0729 AC: 11008 AN: 150918 Hom.: 496 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0552

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.0723

Gnomad SAS AF: 0.0741

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0547

Gnomad OTH AF: 0.0588

GnomAD4 exome AF: 0.0590 AC: 81165 AN: 1376250 Hom.: 2622 Cov.: 39 AF XY: 0.0593 AC XY: 40278 AN XY: 679330

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.0547

Gnomad4 ASJ exome AF: 0.0474

Gnomad4 EAS exome AF: 0.0693

Gnomad4 SAS exome AF: 0.0798

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.0550

Gnomad4 OTH exome AF: 0.0593

GnomAD4 genome AF: 0.0731 AC: 11043 AN: 151026 Hom.: 500 Cov.: 31 AF XY: 0.0748 AC XY: 5508 AN XY: 73676

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0554

Gnomad4 ASJ AF: 0.0510

Gnomad4 EAS AF: 0.0729

Gnomad4 SAS AF: 0.0740

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.0547

Gnomad4 OTH AF: 0.0663

Alfa AF: 0.0758 Hom.: 95

Bravo AF: 0.0723

Asia WGS AF: 0.126 AC: 436 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.47
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9895829; hg19: chr17-7578679; COSMIC: COSV53475599; COSMIC: COSV53475599;