dbSNP rs17880604: TP53:c.673-36G>C (chr17-7674326-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_000546.6(TP53):c.673-36G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,303,868 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 17 hom., cov: 30)

Exomes 𝑓: 0.016 ( 206 hom. )

Consequence

TP53
NM_000546.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.50

Publications

24 publications found

Variant links:

COSMIC-nc: COSV52683791

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 17-7674326-C-G is Benign according to our data. Variant chr17-7674326-C-G is described in ClinVar as Benign. ClinVar VariationId is 221184.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 = 0.0117 (1760/150704) while in subpopulation NFE AF = 0.0193 (1308/67818). AF 95% confidence interval is 0.0184. There are 17 homozygotes in GnomAd4. There are 815 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 1760 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	Effect	Exon Rank	Protein	UniProt
TP53	NM_000546.6	MANE Select	c.673-36G>C	intron	N/A	NP_000537.3
TP53	NM_001126112.3		c.673-36G>C	intron	N/A	NP_001119584.1	K7PPA8
TP53	NM_001407262.1		c.673-36G>C	intron	N/A	NP_001394191.1	K7PPA8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TP53	ENST00000269305.9	TSL:1 MANE Select	c.673-36G>C	intron	N/A	ENSP00000269305.4	P04637-1
TP53	ENST00000445888.6	TSL:1	c.673-36G>C	intron	N/A	ENSP00000391478.2	P04637-1
TP53	ENST00000610292.4	TSL:1	c.556-36G>C	intron	N/A	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1760

AN:

150688

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.0286

Gnomad AMR

AF:

0.00970

Gnomad ASJ

AF:

0.0145

Gnomad EAS

AF:

0.000390

Gnomad SAS

AF:

0.00524

Gnomad FIN

AF:

0.00539

Gnomad MID

AF:

0.0392

Gnomad NFE

AF:

0.0193

Gnomad OTH

AF:

0.0131

GnomAD2 exomes

AF:

0.0122

AC:

3054

AN:

250078

AF XY:

0.0126

show subpopulations

Gnomad AFR exome

AF:

0.00247

Gnomad AMR exome

AF:

0.00709

Gnomad ASJ exome

AF:

0.0166

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00452

Gnomad NFE exome

AF:

0.0202

Gnomad OTH exome

AF:

0.0149

GnomAD4 exome

AF:

0.0160

AC:

18466

AN:

1153164

Hom.:

206

Cov.:

AF XY:

0.0158

AC XY:

9282

AN XY:

587594

show subpopulations

African (AFR)

AF:

0.00291

AC:

AN:

27458

American (AMR)

AF:

0.00760

AC:

336

AN:

44222

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

382

AN:

24148

East Asian (EAS)

AF:

0.0000525

AC:

AN:

38060

South Asian (SAS)

AF:

0.00482

AC:

386

AN:

80120

European-Finnish (FIN)

AF:

0.00542

AC:

286

AN:

52750

Middle Eastern (MID)

AF:

0.0368

AC:

186

AN:

5054

European-Non Finnish (NFE)

AF:

0.0192

AC:

15975

AN:

831212

Other (OTH)

AF:

0.0166

AC:

833

AN:

50140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

921

1841

2762

3682

4603

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.0117

AC:

1760

AN:

150704

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

815

AN XY:

73432

show subpopulations

African (AFR)

AF:

0.00268

AC:

110

AN:

41104

American (AMR)

AF:

0.00969

AC:

147

AN:

15166

Ashkenazi Jewish (ASJ)

AF:

0.0145

AC:

AN:

3460

East Asian (EAS)

AF:

0.000391

AC:

AN:

5114

South Asian (SAS)

AF:

0.00526

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.00539

AC:

AN:

10024

Middle Eastern (MID)

AF:

0.0393

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0193

AC:

1308

AN:

67818

Other (OTH)

AF:

0.0130

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

169

253

338

422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00774

Hom.:

Bravo

AF:

0.0113

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Li-Fraumeni syndrome 1 (3)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

not specified (2)

Hereditary breast ovarian cancer syndrome (1)

Li-Fraumeni syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.017

(source)

DANN

Benign

0.68

PhyloP100

-1.5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over