ENST00000359597.8:c.1010G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The ENST00000359597.8(TP53):c.1010G>C(p.Arg337Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 649,822 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.0060 ( 10 hom., cov: 31)

Exomes 𝑓: 0.00056 ( 1 hom. )

Consequence

TP53
ENST00000359597.8 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 0.721

Publications

3 publications found

Variant links:

COSMIC-nc: COSV53035811

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

TP53 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005035609).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.006 (912/152028) while in subpopulation AFR AF = 0.0211 (875/41478). AF 95% confidence interval is 0.0199. There are 10 homozygotes in GnomAd4. There are 429 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 912 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
TP53	ENST00000359597.8 link	c.1010G>C	p.Arg337Thr	missense_variant	Exon 9 of 9	1	ENSP00000352610.4	J3KP33
TP53	ENST00000413465.6 link	c.783-4214G>C		intron_variant	Intron 6 of 6	1	ENSP00000410739.2	E7EQX7
TP53	ENST00000714356.1 link	c.1000G>C	p.Gly334Arg	missense_variant	Exon 10 of 10		ENSP00000519623.1
TP53	ENST00000635293.1 link	n.*274+674G>C		intron_variant	Intron 11 of 11	5	ENSP00000488924.1	A0A0U1RQC9

Frequencies

GnomAD3 genomes

AF:

0.00600

AC:

912

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000545

AC:

AN:

99062

AF XY:

0.000471

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.000414

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000250

Gnomad OTH exome

AF:

0.000667

GnomAD4 exome

AF:

0.000556

AC:

277

AN:

497794

Hom.:

Cov.:

AF XY:

0.000462

AC XY:

125

AN XY:

270802

show subpopulations

African (AFR)

AF:

0.0180

AC:

236

AN:

13128

American (AMR)

AF:

0.000329

AC:

AN:

27324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18624

East Asian (EAS)

AF:

0.00

AC:

AN:

28686

South Asian (SAS)

AF:

0.0000372

AC:

AN:

53790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32414

Middle Eastern (MID)

AF:

0.000254

AC:

AN:

3936

European-Non Finnish (NFE)

AF:

0.0000137

AC:

AN:

291574

Other (OTH)

AF:

0.000883

AC:

AN:

28318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00600

AC:

912

AN:

152028

Hom.:

Cov.:

AF XY:

0.00577

AC XY:

429

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0211

AC:

875

AN:

41478

American (AMR)

AF:

0.00184

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000736

AC:

AN:

67976

Other (OTH)

AF:

0.00190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00367

Hom.:

Bravo

AF:

0.00687

ExAC

AF:

0.000591

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

2.3

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.017

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0050

MetaSVM

Uncertain

0.54

PhyloP100

0.72

PROVEAN

Benign

-1.4

REVEL

Benign

0.22

Sift

Uncertain

0.019

Sift4G

Uncertain

0.015

Vest4

0.19

MVP

0.71

ClinPred

0.0082

GERP RS

0.43

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over