rs12947788

Variant names:

• chr17-7674109-G-A
• rs12947788
• NM_000546.6:c.782+72C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7674109-G-A
• chr17-7674109-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000546.6(TP53):​c.782+72C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0995 in 1,155,766 control chromosomes in the GnomAD database, including 7,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1035 hom., cov: 31)
  • Exomes 𝑓: 0.099 (6761 hom.)
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.189
• Publications: 52 publications found

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]

TP53 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-7674109-G-A is Benign according to our data. Variant chr17-7674109-G-A is described in ClinVar as Benign. ClinVar VariationId is 1243351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.782+72C>T		intron_variant	Intron 7 of 10	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.782+72C>T		intron_variant	Intron 7 of 10	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15808 AN: 151834 Hom.: 1038 Cov.: 31

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0516

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.0909

GnomAD4 exome AF: 0.0988 AC: 99213 AN: 1003814 Hom.: 6761 AF XY: 0.102 AC XY: 53065 AN XY: 518090

African (AFR) AF: 0.121 AC: 2968 AN: 24524

American (AMR) AF: 0.147 AC: 6238 AN: 42446

Ashkenazi Jewish (ASJ) AF: 0.0693 AC: 1605 AN: 23168

East Asian (EAS) AF: 0.301 AC: 11304 AN: 37514

South Asian (SAS) AF: 0.199 AC: 15215 AN: 76484

European-Finnish (FIN) AF: 0.0542 AC: 2852 AN: 52608

Middle Eastern (MID) AF: 0.0677 AC: 283 AN: 4182

European-Non Finnish (NFE) AF: 0.0778 AC: 54247 AN: 697578

Other (OTH) AF: 0.0993 AC: 4501 AN: 45310

GnomAD4 genome AF: 0.104 AC: 15824 AN: 151952 Hom.: 1035 Cov.: 31 AF XY: 0.106 AC XY: 7852 AN XY: 74276

African (AFR) AF: 0.119 AC: 4913 AN: 41442

American (AMR) AF: 0.119 AC: 1808 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3468

East Asian (EAS) AF: 0.322 AC: 1645 AN: 5116

South Asian (SAS) AF: 0.197 AC: 949 AN: 4814

European-Finnish (FIN) AF: 0.0516 AC: 546 AN: 10586

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0803 AC: 5456 AN: 67974

Other (OTH) AF: 0.0938 AC: 198 AN: 2112

Alfa AF: 0.0944 Hom.: 96

Bravo AF: 0.108

Asia WGS AF: 0.238 AC: 824 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome 1 Benign:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.69
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12947788; hg19: chr17-7577427; COSMIC: COSV52747994; COSMIC: COSV52747994;