chr17-7675353-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000504937.5(TP53):c.-138G>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 0.0171 in 1,531,386 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 25 hom., cov: 31)

Exomes 𝑓: 0.018 ( 239 hom. )

Consequence

TP53
ENST00000504937.5 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.39

Publications

31 publications found

Variant links:

COSMIC-nc: COSV104370796

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 17-7675353-C-T is Benign according to our data. Variant chr17-7675353-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 670316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0129 (1951/151066) while in subpopulation NFE AF = 0.0206 (1397/67894). AF 95% confidence interval is 0.0197. There are 25 homozygotes in GnomAd4. There are 942 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1951 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.376-117G>A		intron_variant	Intron 4 of 10	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.376-117G>A		intron_variant	Intron 4 of 10	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1950

AN:

151004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00366

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00529

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.000391

Gnomad SAS

AF:

0.00334

Gnomad FIN

AF:

0.0267

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.0206

Gnomad OTH

AF:

0.00674

GnomAD4 exome

AF:

0.0176

AC:

24244

AN:

1380320

Hom.:

239

Cov.:

AF XY:

0.0174

AC XY:

11853

AN XY:

681334

show subpopulations

African (AFR)

AF:

0.00262

AC:

AN:

31320

American (AMR)

AF:

0.00515

AC:

180

AN:

34972

Ashkenazi Jewish (ASJ)

AF:

0.00591

AC:

146

AN:

24718

East Asian (EAS)

AF:

0.00131

AC:

AN:

35742

South Asian (SAS)

AF:

0.00405

AC:

317

AN:

78218

European-Finnish (FIN)

AF:

0.0249

AC:

906

AN:

36410

Middle Eastern (MID)

AF:

0.00283

AC:

AN:

4246

European-Non Finnish (NFE)

AF:

0.0203

AC:

21873

AN:

1077096

Other (OTH)

AF:

0.0118

AC:

681

AN:

57598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

1000

2000

2999

3999

4999

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

808

1616

2424

3232

4040

<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:

0.0129

AC:

1951

AN:

151066

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

942

AN XY:

73698

show subpopulations

African (AFR)

AF:

0.00367

AC:

151

AN:

41104

American (AMR)

AF:

0.00528

AC:

AN:

15148

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3468

East Asian (EAS)

AF:

0.000392

AC:

AN:

5100

South Asian (SAS)

AF:

0.00335

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.0267

AC:

275

AN:

10298

Middle Eastern (MID)

AF:

0.00355

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0206

AC:

1397

AN:

67894

Other (OTH)

AF:

0.00670

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

192

287

383

479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0150

Hom.:

Bravo

AF:

0.0108

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 15, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.25

(source)

DANN

Benign

0.57

PhyloP100

-3.4

PromoterAI

-0.018

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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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