chr17-7684581-T-C

Variant names:

• chr17-7684581-T-C
• rs17881035
• NM_000546.6:c.-29+2796A>G

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+2796A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 151,826 control chromosomes in the GnomAD database, including 1,788 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 0.13 (1788 hom., cov: 31)
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.354
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.-29+2796A>G		intron	N/A	NP_000537.3
	TP53	NM_001126112.3		c.-26+2796A>G		intron	N/A	NP_001119584.1
	TP53	NM_001407262.1		c.-132+2796A>G		intron	N/A	NP_001394191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.-29+2796A>G		intron	N/A	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.-26+2796A>G		intron	N/A	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.-263+2796A>G		intron	N/A	ENSP00000478219.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 19993 AN: 151708 Hom.: 1787 Cov.: 31

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.0562

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.0451

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0714

Gnomad OTH AF: 0.117

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

GnomAD4 genome AF: 0.132 AC: 20018 AN: 151826 Hom.: 1788 Cov.: 31 AF XY: 0.132 AC XY: 9828 AN XY: 74192

African (AFR) AF: 0.230 AC: 9533 AN: 41392

American (AMR) AF: 0.132 AC: 2003 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 279 AN: 3468

East Asian (EAS) AF: 0.305 AC: 1566 AN: 5142

South Asian (SAS) AF: 0.205 AC: 989 AN: 4816

European-Finnish (FIN) AF: 0.0451 AC: 475 AN: 10522

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0714 AC: 4851 AN: 67972

Other (OTH) AF: 0.119 AC: 250 AN: 2106

Alfa AF: 0.0937 Hom.: 190

Bravo AF: 0.140

Asia WGS AF: 0.246 AC: 853 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	7.2
DANN	Benign	0.75
PhyloP100		0.35
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: rs17881035; hg19: chr17-7587899;