17-7666228-C-G

Variant names:

• chr17-7666228-C-G
• rs144366923
• ENST00000359597.8:c.1010G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000359597.8(TP53):​c.1010G>C​(p.Arg337Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 649,822 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0060 (10 hom., cov: 31)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: TP53 ENST00000359597.8 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.721

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]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005035609).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.006 (912/152028) while in subpopulation AFR AF = 0.0211 (875/41478). AF 95% confidence interval is 0.0199. There are 10 homozygotes in GnomAd4. There are 429 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 912 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000359597.8	c.1010G>C	p.Arg337Thr	missense_variant	Exon 9 of 9	1		ENSP00000352610.4
TP53	ENST00000413465.6	c.783-4214G>C		intron_variant	Intron 6 of 6	1		ENSP00000410739.2
TP53	ENST00000635293.1	n.*274+674G>C		intron_variant	Intron 11 of 11	5		ENSP00000488924.1

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 912 AN: 151910 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

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: 0.0000735

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000545 AC: 54 AN: 99062 AF XY: 0.000471

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.000414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.000667

GnomAD4 exome AF: 0.000556 AC: 277 AN: 497794 Hom.: 1 Cov.: 0 AF XY: 0.000462 AC XY: 125 AN XY: 270802

Gnomad4 AFR exome AF: 0.0180 AC: 236 AN: 13128

Gnomad4 AMR exome AF: 0.000329 AC: 9 AN: 27324

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 18624

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 28686

Gnomad4 SAS exome AF: 0.0000372 AC: 2 AN: 53790

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 32414

Gnomad4 NFE exome AF: 0.0000137 AC: 4 AN: 291574

Gnomad4 Remaining exome AF: 0.000883 AC: 25 AN: 28318

GnomAD4 genome AF: 0.00600 AC: 912 AN: 152028 Hom.: 10 Cov.: 31 AF XY: 0.00577 AC XY: 429 AN XY: 74314

Gnomad4 AFR AF: 0.0211 AC: 0.0210955 AN: 0.0210955

Gnomad4 AMR AF: 0.00184 AC: 0.00183727 AN: 0.00183727

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000736 AC: 0.0000735554 AN: 0.0000735554

Gnomad4 OTH AF: 0.00190 AC: 0.00189934 AN: 0.00189934

Alfa AF: 0.00367 Hom.: 1

Bravo AF: 0.00687

ExAC AF: 0.000591 AC: 9

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	2.3
DANN	Benign	0.55
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0050	T
MetaSVM	Uncertain	0.54	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.22
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.015	D
Vest4		0.19
MVP		0.71
ClinPred		0.0082	T
GERP RS		0.43
Mutation Taster		=97/3	polymorphism

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs144366923; hg19: chr17-7569546; COSMIC: COSV53035811;