ENST00000504937.5:c.-112G>A

Variant names:

• chr17-7675327-C-T
• rs2909430
• ENST00000504937.5:c.-112G>A

Variant summary

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

The ENST00000504937.5(TP53):​c.-112G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.864 in 1,549,438 control chromosomes in the GnomAD database, including 580,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53539 hom., cov: 29)
  • Exomes 𝑓: 0.87 (526869 hom.)
• Consequence: TP53 ENST00000504937.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.320
• Publications: 80 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=-0.87).
• BP6: Variant 17-7675327-C-T is Benign according to our data. Variant chr17-7675327-C-T is described in ClinVar as Benign. ClinVar VariationId is 440348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000504937.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.376-91G>A		intron	N/A	NP_000537.3
	TP53	NM_001126112.3		c.376-91G>A		intron	N/A	NP_001119584.1
	TP53	NM_001407262.1		c.376-91G>A		intron	N/A	NP_001394191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000504937.5	TSL:1	c.-112G>A		5_prime_UTR	Exon 1 of 7	ENSP00000481179.1
	TP53	ENST00000619186.4	TSL:1	c.-193G>A		5_prime_UTR	Exon 1 of 7	ENSP00000484375.1
	TP53	ENST00000504290.5	TSL:1	c.-112G>A		5_prime_UTR	Exon 1 of 8	ENSP00000484409.1

Frequencies

GnomAD3 genomes AF: 0.837 AC: 126886 AN: 151524 Hom.: 53502 Cov.: 29

Gnomad AFR AF: 0.737

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.841

Gnomad EAS AF: 0.967

Gnomad SAS AF: 0.800

Gnomad FIN AF: 0.889

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.873

Gnomad OTH AF: 0.837

GnomAD4 exome AF: 0.867 AC: 1212266 AN: 1397800 Hom.: 526869 Cov.: 46 AF XY: 0.865 AC XY: 597421 AN XY: 691020

African (AFR) AF: 0.727 AC: 23218 AN: 31936

American (AMR) AF: 0.919 AC: 33131 AN: 36048

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 21052 AN: 25248

East Asian (EAS) AF: 0.972 AC: 35255 AN: 36256

South Asian (SAS) AF: 0.793 AC: 63391 AN: 79964

European-Finnish (FIN) AF: 0.890 AC: 36455 AN: 40954

Middle Eastern (MID) AF: 0.716 AC: 3418 AN: 4772

European-Non Finnish (NFE) AF: 0.873 AC: 946163 AN: 1084330

Other (OTH) AF: 0.861 AC: 50183 AN: 58292

GnomAD4 genome AF: 0.837 AC: 126969 AN: 151638 Hom.: 53539 Cov.: 29 AF XY: 0.837 AC XY: 62038 AN XY: 74088

African (AFR) AF: 0.737 AC: 30372 AN: 41238

American (AMR) AF: 0.887 AC: 13498 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.841 AC: 2915 AN: 3468

East Asian (EAS) AF: 0.967 AC: 4988 AN: 5160

South Asian (SAS) AF: 0.800 AC: 3852 AN: 4816

European-Finnish (FIN) AF: 0.889 AC: 9297 AN: 10452

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.873 AC: 59315 AN: 67978

Other (OTH) AF: 0.839 AC: 1769 AN: 2108

Alfa AF: 0.860 Hom.: 128987

Bravo AF: 0.835

Asia WGS AF: 0.887 AC: 3084 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Jul 02, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.0
DANN	Benign	0.76
PhyloP100		0.32
PromoterAI		-0.088	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2909430; hg19: chr17-7578645; COSMIC: COSV52668782;