rs34949160

Positions:

• chr17-7674828-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000546.6(TP53):​c.672+31A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 1,599,970 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (79 hom.)
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.800

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=-0.86).
• BP6: Variant 17-7674828-T-C is Benign according to our data. Variant chr17-7674828-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 133420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00541 (823/152218) while in subpopulation SAS AF= 0.0226 (109/4816). AF 95% confidence interval is 0.0192. There are 6 homozygotes in gnomad4. There are 404 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 823 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.672+31A>G		intron_variant		ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.672+31A>G		intron_variant		1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.00542 AC: 824 AN: 152100 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00709

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00727 AC: 1796 AN: 247126 Hom.: 13 AF XY: 0.00796 AC XY: 1064 AN XY: 133676

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0180

Gnomad FIN exome AF: 0.00118

Gnomad NFE exome AF: 0.00733

Gnomad OTH exome AF: 0.00777

GnomAD4 exome AF: 0.00798 AC: 11560 AN: 1447752 Hom.: 79 Cov.: 31 AF XY: 0.00829 AC XY: 5975 AN XY: 720994

Gnomad4 AFR exome AF: 0.00154

Gnomad4 AMR exome AF: 0.00363

Gnomad4 ASJ exome AF: 0.0214

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0182

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.00774

Gnomad4 OTH exome AF: 0.00845

GnomAD4 genome AF: 0.00541 AC: 823 AN: 152218 Hom.: 6 Cov.: 33 AF XY: 0.00543 AC XY: 404 AN XY: 74418

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00709

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00846 Hom.: 2

Bravo AF: 0.00496

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Li-Fraumeni syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2018

This variant is associated with the following publications: (PMID: 24728327) -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely 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	-0.86
CADD	Benign	5.2
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34949160; hg19: chr17-7578146; COSMIC: COSV52745548; COSMIC: COSV52745548;