rs8079544

Variant names:

• chr17-7676734-C-T
• rs8079544
• NM_000546.6:c.-28-112G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000546.6(TP53):​c.-28-112G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0626 in 768,624 control chromosomes in the GnomAD database, including 1,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (499 hom., cov: 31)
  • Exomes 𝑓: 0.060 (1293 hom.)
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.69
• Publications: 49 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 17-7676734-C-T is Benign according to our data. Variant chr17-7676734-C-T is described in ClinVar as Benign. ClinVar VariationId is 1292419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.-28-112G>A		intron_variant	Intron 1 of 10	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.-28-112G>A		intron_variant	Intron 1 of 10	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.0726 AC: 11035 AN: 152000 Hom.: 497 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0550

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.0653

Gnomad SAS AF: 0.0670

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0543

Gnomad OTH AF: 0.0575

GnomAD4 exome AF: 0.0601 AC: 37066 AN: 616506 Hom.: 1293 AF XY: 0.0599 AC XY: 19688 AN XY: 328820

African (AFR) AF: 0.100 AC: 1691 AN: 16856

American (AMR) AF: 0.0543 AC: 1884 AN: 34692

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 989 AN: 20318

East Asian (EAS) AF: 0.0653 AC: 2107 AN: 32244

South Asian (SAS) AF: 0.0739 AC: 4689 AN: 63452

European-Finnish (FIN) AF: 0.101 AC: 3827 AN: 37898

Middle Eastern (MID) AF: 0.0175 AC: 56 AN: 3194

European-Non Finnish (NFE) AF: 0.0531 AC: 19929 AN: 375298

Other (OTH) AF: 0.0582 AC: 1894 AN: 32554

GnomAD4 genome AF: 0.0727 AC: 11065 AN: 152118 Hom.: 499 Cov.: 31 AF XY: 0.0743 AC XY: 5523 AN XY: 74366

African (AFR) AF: 0.104 AC: 4331 AN: 41490

American (AMR) AF: 0.0552 AC: 843 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 177 AN: 3472

East Asian (EAS) AF: 0.0658 AC: 341 AN: 5180

South Asian (SAS) AF: 0.0670 AC: 323 AN: 4820

European-Finnish (FIN) AF: 0.106 AC: 1123 AN: 10580

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0544 AC: 3696 AN: 68000

Other (OTH) AF: 0.0621 AC: 131 AN: 2108

Alfa AF: 0.0577 Hom.: 477

Bravo AF: 0.0718

Asia WGS AF: 0.121 AC: 419 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.69
DANN	Benign	0.26
PhyloP100		-5.7
PromoterAI		-0.029	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8079544; hg19: chr17-7580052; COSMIC: COSV107296019; COSMIC: COSV107296019;