rs9893249

Variant names:

• chr17-7666871-T-C
• rs9893249
• ENST00000359597.8:c.994-627A>G

Variant summary

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

The ENST00000359597.8(TP53):​c.994-627A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 152,184 control chromosomes in the GnomAD database, including 10,710 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 0.37 (10701 hom., cov: 32)
  • Exomes 𝑓: 0.41 (9 hom.)
• Consequence: TP53 ENST00000359597.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0700
• Publications: 7 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000359597.8	c.994-627A>G		intron_variant	Intron 8 of 8	1		ENSP00000352610.4
TP53	ENST00000413465.6	c.783-4857A>G		intron_variant	Intron 6 of 6	1		ENSP00000410739.2
TP53	ENST00000714356.1	c.984-627A>G		intron_variant	Intron 9 of 9			ENSP00000519623.1
TP53	ENST00000635293.1	n.*274+31A>G		intron_variant	Intron 11 of 11	5		ENSP00000488924.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55535 AN: 151970 Hom.: 10692 Cov.: 32

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.0585

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.330

GnomAD4 exome AF: 0.408 AC: 40 AN: 98 Hom.: 9 Cov.: 0 AF XY: 0.403 AC XY: 25 AN XY: 62

African (AFR) AF: 0.250 AC: 2 AN: 8

American (AMR) AF: 1.00 AC: 2 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 6

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.417 AC: 30 AN: 72

Other (OTH) AF: 0.667 AC: 4 AN: 6

GnomAD4 genome AF: 0.365 AC: 55582 AN: 152086 Hom.: 10701 Cov.: 32 AF XY: 0.359 AC XY: 26657 AN XY: 74336

African (AFR) AF: 0.408 AC: 16924 AN: 41492

American (AMR) AF: 0.277 AC: 4224 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1067 AN: 3472

East Asian (EAS) AF: 0.0590 AC: 305 AN: 5166

South Asian (SAS) AF: 0.186 AC: 896 AN: 4820

European-Finnish (FIN) AF: 0.422 AC: 4457 AN: 10570

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.390 AC: 26519 AN: 67984

Other (OTH) AF: 0.333 AC: 704 AN: 2114

Alfa AF: 0.385 Hom.: 2702

Bravo AF: 0.354

Asia WGS AF: 0.195 AC: 681 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.58
PhyloP100		0.070
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: rs9893249; hg19: chr17-7570189;