dbSNP rs1800372: TP53:p.Arg213Arg (chr17-7674892-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000546.6(TP53):c.639A>G(p.Arg213Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,614,122 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R213R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 20 hom., cov: 33)

Exomes 𝑓: 0.015 ( 186 hom. )

Consequence

TP53
NM_000546.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:27

Conservation

PhyloP100: -3.23

Publications

111 publications found

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 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 17-7674892-T-C is Benign according to our data. Variant chr17-7674892-T-C is described in ClinVar as Benign. ClinVar VariationId is 43591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.23 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0125 (1904/152238) while in subpopulation AMR AF = 0.0201 (307/15284). AF 95% confidence interval is 0.0182. There are 20 homozygotes in GnomAd4. There are 867 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1904 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TP53	NM_000546.6	MANE Select	c.639A>G	p.Arg213Arg	synonymous	Exon 6 of 11	NP_000537.3
TP53	NM_001126112.3		c.639A>G	p.Arg213Arg	synonymous	Exon 6 of 11	NP_001119584.1	K7PPA8
TP53	NM_001407262.1		c.639A>G	p.Arg213Arg	synonymous	Exon 7 of 12	NP_001394191.1	K7PPA8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TP53	ENST00000269305.9	TSL:1 MANE Select	c.639A>G	p.Arg213Arg	synonymous	Exon 6 of 11	ENSP00000269305.4	P04637-1
TP53	ENST00000445888.6	TSL:1	c.639A>G	p.Arg213Arg	synonymous	Exon 6 of 11	ENSP00000391478.2	P04637-1
TP53	ENST00000610292.4	TSL:1	c.522A>G	p.Arg174Arg	synonymous	Exon 5 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1904

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.0372

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0177

Gnomad OTH

AF:

0.0216

GnomAD2 exomes

AF:

0.0126

AC:

3163

AN:

251468

AF XY:

0.0127

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.0337

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00457

Gnomad NFE exome

AF:

0.0177

Gnomad OTH exome

AF:

0.0230

GnomAD4 exome

AF:

0.0146

AC:

21360

AN:

1461884

Hom.:

186

Cov.:

AF XY:

0.0145

AC XY:

10512

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

33480

American (AMR)

AF:

0.0139

AC:

620

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0344

AC:

899

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00231

AC:

199

AN:

86256

European-Finnish (FIN)

AF:

0.00492

AC:

263

AN:

53420

Middle Eastern (MID)

AF:

0.0342

AC:

197

AN:

5768

European-Non Finnish (NFE)

AF:

0.0163

AC:

18125

AN:

1112004

Other (OTH)

AF:

0.0161

AC:

970

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1271

2543

3814

5086

6357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

660

1320

1980

2640

3300

<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:

0.0125

AC:

1904

AN:

152238

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

867

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00325

AC:

135

AN:

41546

American (AMR)

AF:

0.0201

AC:

307

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0372

AC:

129

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00249

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0177

AC:

1207

AN:

68004

Other (OTH)

AF:

0.0213

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

104

208

312

416

520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0166

Hom.:

Bravo

AF:

0.0137

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0211

EpiControl

AF:

0.0232

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Li-Fraumeni syndrome 1 (7)

not provided (5)

Hereditary cancer-predisposing syndrome (4)

Hereditary breast ovarian cancer syndrome (1)

Li-Fraumeni syndrome (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

7.9

(source)

DANN

Benign

0.69

PhyloP100

-3.2

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over