rs17880847

Variant names:

• chr17-7670579-T-A
• rs17880847
• NM_000546.6:c.1100+30A>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7670579-T-A
• chr17-7670579-T-C
• chr17-7670579-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000546.6(TP53):​c.1100+30A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,511,366 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (111 hom.)
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.934
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-7670579-T-A is Benign according to our data. Variant chr17-7670579-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 810938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00899 (1363/151652) while in subpopulation NFE AF = 0.0147 (1000/67910). AF 95% confidence interval is 0.014. There are 7 homozygotes in GnomAd4. There are 623 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1363 AD gene.

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.1100+30A>T		intron	N/A	NP_000537.3
	TP53	NM_001126112.3		c.1100+30A>T		intron	N/A	NP_001119584.1
	TP53	NM_001407262.1		c.1100+30A>T		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.1100+30A>T		intron	N/A	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.1100+30A>T		intron	N/A	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.983+30A>T		intron	N/A	ENSP00000478219.1

Frequencies

GnomAD3 genomes AF: 0.00898 AC: 1361 AN: 151532 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00973

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.00285

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00945 AC: 2222 AN: 235112 AF XY: 0.00943

Gnomad AFR exome AF: 0.00171

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00401

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0121 AC: 16492 AN: 1359714 Hom.: 111 Cov.: 20 AF XY: 0.0120 AC XY: 8166 AN XY: 679756

African (AFR) AF: 0.00133 AC: 42 AN: 31492

American (AMR) AF: 0.0110 AC: 472 AN: 42794

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 375 AN: 25192

East Asian (EAS) AF: 0.0000767 AC: 3 AN: 39088

South Asian (SAS) AF: 0.00223 AC: 185 AN: 82982

European-Finnish (FIN) AF: 0.00438 AC: 231 AN: 52684

Middle Eastern (MID) AF: 0.00777 AC: 42 AN: 5406

European-Non Finnish (NFE) AF: 0.0142 AC: 14524 AN: 1023066

Other (OTH) AF: 0.0108 AC: 618 AN: 57010

GnomAD4 genome AF: 0.00899 AC: 1363 AN: 151652 Hom.: 7 Cov.: 32 AF XY: 0.00841 AC XY: 623 AN XY: 74116

African (AFR) AF: 0.00216 AC: 89 AN: 41288

American (AMR) AF: 0.00979 AC: 149 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00250 AC: 12 AN: 4800

European-Finnish (FIN) AF: 0.00285 AC: 30 AN: 10522

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 1000 AN: 67910

Other (OTH) AF: 0.0142 AC: 30 AN: 2108

Alfa AF: 0.00865 Hom.: 0

Bravo AF: 0.00972

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Li-Fraumeni syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.11
DANN	Benign	0.79
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism

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: rs17880847; hg19: chr17-7573897; COSMIC: COSV53152345;