ENST00000359597.8:c.994-1261C>G

Variant names:

• chr17-7667505-G-C
• rs9914052
• ENST00000359597.8:c.994-1261C>G

Variant summary

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

The ENST00000359597.8(TP53):​c.994-1261C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 152,228 control chromosomes in the GnomAD database, including 1,965 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 0.12 (1965 hom., cov: 30)
  • Exomes 𝑓: 0.047 (0 hom.)
• Consequence: TP53 ENST00000359597.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.203
• Publications: 3 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=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.264 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000359597.8	TSL:1	c.994-1261C>G		intron	N/A	ENSP00000352610.4
	TP53	ENST00000413465.6	TSL:1	c.783-5491C>G		intron	N/A	ENSP00000410739.2
	TP53	ENST00000714356.1		c.984-1261C>G		intron	N/A	ENSP00000519623.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18053 AN: 152024 Hom.: 1959 Cov.: 30

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0685

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0445

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.0465 AC: 4 AN: 86 Hom.: 0 AF XY: 0.0645 AC XY: 4 AN XY: 62

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.250 AC: 1 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0417 AC: 3 AN: 72

Other (OTH) AF: 0.00 AC: 0 AN: 6

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0618289), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.119 AC: 18094 AN: 152142 Hom.: 1965 Cov.: 30 AF XY: 0.118 AC XY: 8780 AN XY: 74390

African (AFR) AF: 0.268 AC: 11120 AN: 41478

American (AMR) AF: 0.0684 AC: 1046 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.276 AC: 1421 AN: 5154

South Asian (SAS) AF: 0.192 AC: 925 AN: 4824

European-Finnish (FIN) AF: 0.0155 AC: 165 AN: 10616

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0445 AC: 3028 AN: 67986

Other (OTH) AF: 0.109 AC: 230 AN: 2114

Alfa AF: 0.0262 Hom.: 28

Bravo AF: 0.130

Asia WGS AF: 0.233 AC: 809 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.6
DANN	Benign	0.85
PhyloP100		0.20
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: rs9914052; hg19: chr17-7570823;