rs17882227

Variant names:

• chr17-7685242-A-G
• rs17882227
• NM_000546.6:c.-29+2135T>C

Variant summary

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

The NM_000546.6(TP53):​c.-29+2135T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 152,122 control chromosomes in the GnomAD database, including 2,310 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 0.15 (2310 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.126
• Publications: 10 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), 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=-0.69).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.-29+2135T>C		intron	N/A	NP_000537.3
	TP53	NM_001126112.3		c.-26+2135T>C		intron	N/A	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.-132+2135T>C		intron	N/A	NP_001394191.1	K7PPA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.-29+2135T>C		intron	N/A	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.-26+2135T>C		intron	N/A	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.-263+2135T>C		intron	N/A	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22434 AN: 152004 Hom.: 2306 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.0806

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.0472

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0760

Gnomad OTH AF: 0.125

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.148 AC: 22468 AN: 152122 Hom.: 2310 Cov.: 32 AF XY: 0.148 AC XY: 10992 AN XY: 74410

African (AFR) AF: 0.275 AC: 11391 AN: 41454

American (AMR) AF: 0.142 AC: 2174 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0806 AC: 280 AN: 3472

East Asian (EAS) AF: 0.306 AC: 1584 AN: 5184

South Asian (SAS) AF: 0.213 AC: 1028 AN: 4826

European-Finnish (FIN) AF: 0.0472 AC: 501 AN: 10612

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0760 AC: 5167 AN: 68000

Other (OTH) AF: 0.127 AC: 268 AN: 2110

Alfa AF: 0.116 Hom.: 250

Bravo AF: 0.157

Asia WGS AF: 0.253 AC: 876 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.7
DANN	Benign	0.86
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs17882227; hg19: chr17-7588560;