rs17880847

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000546.6(TP53):c.1100+30A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,511,366 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0090 ( 7 hom., cov: 32)

Exomes 𝑓: 0.012 ( 111 hom. )

Consequence

TP53
NM_000546.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.934

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 17-7670579-T-A is Benign according to our data. Variant chr17-7670579-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 810938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7670579-T-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00899 (1363/151652) while in subpopulation NFE AF= 0.0147 (1000/67910). AF 95% confidence interval is 0.014. There are 7 homozygotes in gnomad4. There are 623 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1363 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.1100+30A>T		intron_variant		ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.1100+30A>T		intron_variant		1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00898

AC:

1361

AN:

151532

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00216

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00973

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.00285

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0147

Gnomad OTH

AF:

0.0144

GnomAD3 exomes

AF:

0.00945

AC:

2222

AN:

235112

Hom.:

AF XY:

0.00943

AC XY:

1198

AN XY:

127068

show subpopulations

Gnomad AFR exome

AF:

0.00171

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00218

Gnomad FIN exome

AF:

0.00401

Gnomad NFE exome

AF:

0.0136

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.0121

AC:

16492

AN:

1359714

Hom.:

111

Cov.:

AF XY:

0.0120

AC XY:

8166

AN XY:

679756

show subpopulations

Gnomad4 AFR exome

AF:

0.00133

Gnomad4 AMR exome

AF:

0.0110

Gnomad4 ASJ exome

AF:

0.0149

Gnomad4 EAS exome

AF:

0.0000767

Gnomad4 SAS exome

AF:

0.00223

Gnomad4 FIN exome

AF:

0.00438

Gnomad4 NFE exome

AF:

0.0142

Gnomad4 OTH exome

AF:

0.0108

GnomAD4 genome

AF:

0.00899

AC:

1363

AN:

151652

Hom.:

Cov.:

AF XY:

0.00841

AC XY:

623

AN XY:

74116

show subpopulations

Gnomad4 AFR

AF:

0.00216

Gnomad4 AMR

AF:

0.00979

Gnomad4 ASJ

AF:

0.0150

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00250

Gnomad4 FIN

AF:

0.00285

Gnomad4 NFE

AF:

0.0147

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.00865

Hom.:

Bravo

AF:

0.00972

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 31, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Li-Fraumeni syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Hereditary breast ovarian cancer syndrome

Benign:1

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

-0.84

CADD

Benign

0.11

DANN

Benign

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over