ENST00000359597.8:c.994-1518T>C

Variant names:

• chr17-7667762-A-G
• rs9894946
• ENST00000359597.8:c.994-1518T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000359597.8(TP53):​c.994-1518T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 152,210 control chromosomes in the GnomAD database, including 58,506 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (58506 hom., cov: 32)
• Consequence: TP53 ENST00000359597.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.139
• Publications: 24 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359597.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000359597.8	TSL:1	c.994-1518T>C		intron	N/A	ENSP00000352610.4
	TP53	ENST00000413465.6	TSL:1	c.783-5748T>C		intron	N/A	ENSP00000410739.2
	TP53	ENST00000714356.1		c.984-1518T>C		intron	N/A	ENSP00000519623.1

Frequencies

GnomAD3 genomes AF: 0.875 AC: 133032 AN: 152092 Hom.: 58449 Cov.: 32

Gnomad AFR AF: 0.944

Gnomad AMI AF: 0.825

Gnomad AMR AF: 0.900

Gnomad ASJ AF: 0.813

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.846

Gnomad MID AF: 0.669

Gnomad NFE AF: 0.841

Gnomad OTH AF: 0.853

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.875 AC: 133145 AN: 152210 Hom.: 58506 Cov.: 32 AF XY: 0.873 AC XY: 64985 AN XY: 74408

African (AFR) AF: 0.944 AC: 39211 AN: 41554

American (AMR) AF: 0.900 AC: 13759 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 2821 AN: 3470

East Asian (EAS) AF: 0.966 AC: 4979 AN: 5154

South Asian (SAS) AF: 0.722 AC: 3482 AN: 4826

European-Finnish (FIN) AF: 0.846 AC: 8977 AN: 10612

Middle Eastern (MID) AF: 0.661 AC: 193 AN: 292

European-Non Finnish (NFE) AF: 0.841 AC: 57167 AN: 67996

Other (OTH) AF: 0.854 AC: 1804 AN: 2112

Alfa AF: 0.858 Hom.: 16624

Bravo AF: 0.885

Asia WGS AF: 0.879 AC: 3057 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.3
DANN	Benign	0.74
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9894946; hg19: chr17-7571080;