rs8073498

Variant names:

• chr17-7666380-A-C
• rs8073498
• ENST00000359597.8:c.994-136T>G

Variant summary

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

The ENST00000359597.8(TP53):​c.994-136T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 378,424 control chromosomes in the GnomAD database, including 25,260 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 (10683 hom., cov: 31)
  • Exomes 𝑓: 0.34 (14577 hom.)
• Consequence: TP53 ENST00000359597.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388
• Publications: 37 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=-0.98).
• 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.994-136T>G		intron_variant	Intron 8 of 8	1		ENSP00000352610.4
TP53	ENST00000413465.6	c.783-4366T>G		intron_variant	Intron 6 of 6	1		ENSP00000410739.2
TP53	ENST00000714356.1	c.984-136T>G		intron_variant	Intron 9 of 9			ENSP00000519623.1
TP53	ENST00000635293.1	n.*274+522T>G		intron_variant	Intron 11 of 11	5		ENSP00000488924.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55468 AN: 151828 Hom.: 10673 Cov.: 31

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.0584

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.329

GnomAD4 exome AF: 0.336 AC: 76196 AN: 226478 Hom.: 14577 AF XY: 0.333 AC XY: 40110 AN XY: 120476

African (AFR) AF: 0.407 AC: 2324 AN: 5708

American (AMR) AF: 0.220 AC: 1469 AN: 6680

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 2334 AN: 7684

East Asian (EAS) AF: 0.0349 AC: 635 AN: 18188

South Asian (SAS) AF: 0.198 AC: 2831 AN: 14292

European-Finnish (FIN) AF: 0.428 AC: 7510 AN: 17530

Middle Eastern (MID) AF: 0.235 AC: 648 AN: 2760

European-Non Finnish (NFE) AF: 0.385 AC: 53769 AN: 139772

Other (OTH) AF: 0.337 AC: 4676 AN: 13864

GnomAD4 genome AF: 0.365 AC: 55517 AN: 151946 Hom.: 10683 Cov.: 31 AF XY: 0.358 AC XY: 26609 AN XY: 74260

African (AFR) AF: 0.408 AC: 16919 AN: 41436

American (AMR) AF: 0.276 AC: 4212 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1066 AN: 3470

East Asian (EAS) AF: 0.0589 AC: 305 AN: 5180

South Asian (SAS) AF: 0.186 AC: 897 AN: 4824

European-Finnish (FIN) AF: 0.422 AC: 4448 AN: 10542

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

European-Non Finnish (NFE) AF: 0.390 AC: 26486 AN: 67930

Other (OTH) AF: 0.333 AC: 702 AN: 2110

Alfa AF: 0.369 Hom.: 46663

Bravo AF: 0.354

Asia WGS AF: 0.195 AC: 682 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.8
DANN	Benign	0.71
PhyloP100		-0.39
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: rs8073498; hg19: chr17-7569698; COSMIC: COSV99363901; COSMIC: COSV99363901;