chr17-7673245-A-G

Position:

• chr17-7673245-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1 BP4_Moderate BP6_Very_Strong BS2

The NM_001126113.3(TP53):​c.1015T>C​(p.Cys339Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,426,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TP53 NM_001126113.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.387

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PM1: In a region_of_interest Interaction with HIPK1 (size 270) in uniprot entity P53_HUMAN there are 59 pathogenic changes around while only 5 benign (92%) in NM_001126113.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.23743477).
• BP6: Variant 17-7673245-A-G is Benign according to our data. Variant chr17-7673245-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 492646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.993+290T>C		intron_variant		ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.993+290T>C		intron_variant		1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000505 AC: 9 AN: 178188 Hom.: 0 AF XY: 0.0000211 AC XY: 2 AN XY: 94892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000345

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 15 AN: 1274704 Hom.: 0 Cov.: 19 AF XY: 0.0000110 AC XY: 7 AN XY: 637246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000409

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74310

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000168 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 06, 2017	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 24, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Benign	0.0037	.;T;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.30	T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Uncertain	0.66	D
PROVEAN	Benign	2.5	.;.;N;.
REVEL	Benign	0.26
Sift	Benign	0.13	.;.;T;.
Sift4G	Uncertain	0.050	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.35
MutPred		0.71		.;.;Gain of MoRF binding (P = 0.0052);.;
MVP		0.62
ClinPred		0.018	T
GERP RS		-0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1642789; hg19: chr17-7576563;