rs9895829

Variant names:

• chr17-7675361-A-G
• rs9895829
• ENST00000504937.5:c.-146T>C

Variant summary

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

The ENST00000504937.5(TP53):​c.-146T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,527,276 control chromosomes in the GnomAD database, including 3,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (500 hom., cov: 31)
  • Exomes 𝑓: 0.059 (2622 hom.)
• Consequence: TP53 ENST00000504937.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.545
• Publications: 40 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=-0.9).
• BP6: Variant 17-7675361-A-G is Benign according to our data. Variant chr17-7675361-A-G is described in ClinVar as Benign. ClinVar VariationId is 1245512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.376-125T>C		intron_variant	Intron 4 of 10	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.376-125T>C		intron_variant	Intron 4 of 10	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.0729 AC: 11008 AN: 150918 Hom.: 496 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0552

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.0723

Gnomad SAS AF: 0.0741

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0547

Gnomad OTH AF: 0.0588

GnomAD4 exome AF: 0.0590 AC: 81165 AN: 1376250 Hom.: 2622 Cov.: 39 AF XY: 0.0593 AC XY: 40278 AN XY: 679330

African (AFR) AF: 0.104 AC: 3249 AN: 31140

American (AMR) AF: 0.0547 AC: 1875 AN: 34276

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 1164 AN: 24532

East Asian (EAS) AF: 0.0693 AC: 2473 AN: 35706

South Asian (SAS) AF: 0.0798 AC: 6203 AN: 77750

European-Finnish (FIN) AF: 0.101 AC: 3610 AN: 35760

Middle Eastern (MID) AF: 0.0205 AC: 85 AN: 4150

European-Non Finnish (NFE) AF: 0.0550 AC: 59104 AN: 1075522

Other (OTH) AF: 0.0593 AC: 3402 AN: 57414

GnomAD4 genome AF: 0.0731 AC: 11043 AN: 151026 Hom.: 500 Cov.: 31 AF XY: 0.0748 AC XY: 5508 AN XY: 73676

African (AFR) AF: 0.104 AC: 4275 AN: 41104

American (AMR) AF: 0.0554 AC: 835 AN: 15060

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

East Asian (EAS) AF: 0.0729 AC: 373 AN: 5118

South Asian (SAS) AF: 0.0740 AC: 355 AN: 4796

European-Finnish (FIN) AF: 0.105 AC: 1079 AN: 10300

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0547 AC: 3711 AN: 67876

Other (OTH) AF: 0.0663 AC: 139 AN: 2098

Alfa AF: 0.0627 Hom.: 449

Bravo AF: 0.0723

Asia WGS AF: 0.126 AC: 436 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.47
DANN	Benign	0.57
PhyloP100		0.55
PromoterAI		-0.0031	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9895829; hg19: chr17-7578679; COSMIC: COSV53475599; COSMIC: COSV53475599;