2-24077693-T-C

Position:

• chr2-24077693-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001206802.2(TP53I3):​c.688A>G​(p.Thr230Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,613,872 control chromosomes in the GnomAD database, including 15,905 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1240 hom., cov: 31)
  • Exomes 𝑓: 0.14 (14665 hom.)
• Consequence: TP53I3 NM_001206802.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.574

Genes affected

TP53I3 (HGNC:19373): (tumor protein p53 inducible protein 3) The protein encoded by this gene is similar to oxidoreductases, which are enzymes involved in cellular responses to oxidative stresses and irradiation. This gene is induced by the tumor suppressor p53 and is thought to be involved in p53-mediated cell death. It contains a p53 consensus binding site in its promoter region and a downstream pentanucleotide microsatellite sequence. P53 has been shown to transcriptionally activate this gene by interacting with the downstream pentanucleotide microsatellite sequence. The microsatellite is polymorphic, with a varying number of pentanucleotide repeats directly correlated with the extent of transcriptional activation by p53. It has been suggested that the microsatellite polymorphism may be associated with differential susceptibility to cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

FAM228B (HGNC:24736): (family with sequence similarity 228 member B)

FAM228B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.999871E-4).
• BP6: Variant 2-24077693-T-C is Benign according to our data. Variant chr2-24077693-T-C is described in ClinVar as [Benign]. Clinvar id is 3060882.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53I3	NM_004881.5	c.885A>G	p.Gln295Gln	synonymous_variant	5/5	ENST00000238721.9	NP_004872.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53I3	ENST00000238721.9	c.885A>G	p.Gln295Gln	synonymous_variant	5/5	1	NM_004881.5	ENSP00000238721.4

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17767 AN: 151964 Hom.: 1240 Cov.: 31

Gnomad AFR AF: 0.0703

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0733

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0420

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.123 AC: 30839 AN: 251420 Hom.: 2292 AF XY: 0.128 AC XY: 17446 AN XY: 135878

Gnomad AFR exome AF: 0.0689

Gnomad AMR exome AF: 0.0464

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0439

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.137 AC: 200693 AN: 1461790 Hom.: 14665 Cov.: 33 AF XY: 0.139 AC XY: 100721 AN XY: 727202

Gnomad4 AFR exome AF: 0.0675

Gnomad4 AMR exome AF: 0.0489

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.0335

Gnomad4 SAS exome AF: 0.173

Gnomad4 FIN exome AF: 0.205

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.117 AC: 17759 AN: 152082 Hom.: 1240 Cov.: 31 AF XY: 0.120 AC XY: 8894 AN XY: 74316

Gnomad4 AFR AF: 0.0703

Gnomad4 AMR AF: 0.0731

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.0421

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.226

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.106

Alfa AF: 0.129 Hom.: 2851

Bravo AF: 0.103

TwinsUK AF: 0.143 AC: 531

ALSPAC AF: 0.132 AC: 509

ESP6500AA AF: 0.0729 AC: 321

ESP6500EA AF: 0.141 AC: 1214

ExAC AF: 0.124 AC: 15100

Asia WGS AF: 0.101 AC: 351 AN: 3478

EpiCase AF: 0.138

EpiControl AF: 0.135

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TP53I3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.9
DANN	Uncertain	0.99
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0010	T
MetaSVM	Benign	-0.95	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.015
Sift	Benign	0.20	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.11
ClinPred		0.0081	T
GERP RS		-3.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs10209238; hg19: chr2-24300563; COSMIC: COSV51982087; COSMIC: COSV51982087;