20-388261-A-G

Position:

• chr20-388261-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000217233.9(TRIB3):​c.251A>G​(p.Gln84Arg) variant causes a missense change. The variant allele was found at a frequency of 0.171 in 1,613,002 control chromosomes in the GnomAD database, including 26,855 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2264 hom., cov: 33)
  • Exomes 𝑓: 0.17 (24591 hom.)
• Consequence: TRIB3 ENST00000217233.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05

Genes affected

TRIB3 (HGNC:16228): (tribbles pseudokinase 3) The protein encoded by this gene is a putative protein kinase that is induced by the transcription factor NF-kappaB. The encoded protein is a negative regulator of NF-kappaB and can also sensitize cells to TNF- and TRAIL-induced apoptosis. In addition, this protein can negatively regulate the cell survival serine-threonine kinase AKT1. Differential promoter usage and alternate splicing result in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004573077).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIB3	NM_021158.5	c.251A>G	p.Gln84Arg	missense_variant	2/4	ENST00000217233.9	NP_066981.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIB3	ENST00000217233.9	c.251A>G	p.Gln84Arg	missense_variant	2/4	1	NM_021158.5	ENSP00000217233.3
TRIB3	ENST00000422053.3	c.332A>G	p.Gln111Arg	missense_variant	3/5	2		ENSP00000415416.2
TRIB3	ENST00000449710.5	c.251A>G	p.Gln84Arg	missense_variant	2/4	5		ENSP00000391873.2
TRIB3	ENST00000615226.4	c.251A>G	p.Gln84Arg	missense_variant	4/5	3		ENSP00000478194.2

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25080 AN: 152134 Hom.: 2257 Cov.: 33

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.145

GnomAD3 exomes AF: 0.178 AC: 44325 AN: 248822 Hom.: 4917 AF XY: 0.191 AC XY: 25770 AN XY: 134920

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0782

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.192

Gnomad SAS exome AF: 0.383

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.172 AC: 251193 AN: 1460750 Hom.: 24591 Cov.: 33 AF XY: 0.178 AC XY: 129639 AN XY: 726694

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.0810

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.207

Gnomad4 SAS exome AF: 0.382

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.165 AC: 25109 AN: 152252 Hom.: 2264 Cov.: 33 AF XY: 0.168 AC XY: 12489 AN XY: 74436

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.373

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.146

Alfa AF: 0.155 Hom.: 2855

Bravo AF: 0.152

TwinsUK AF: 0.155 AC: 576

ALSPAC AF: 0.152 AC: 586

ESP6500AA AF: 0.160 AC: 706

ESP6500EA AF: 0.155 AC: 1334

ExAC AF: 0.181 AC: 21957

Asia WGS AF: 0.256 AC: 888 AN: 3478

EpiCase AF: 0.153

EpiControl AF: 0.154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.15
DEOGEN2	Benign	0.24	T;T;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.12	T;T;T;T
MetaRNN	Benign	0.0046	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.6	.;N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	2.1	.;N;N;N
REVEL	Benign	0.078
Sift	Benign	1.0	.;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.050, 0.040
MPC		0.18
ClinPred		0.0036	T
GERP RS		4.5
Varity_R		0.021
gMVP		0.46

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: rs2295490; hg19: chr20-368905; COSMIC: COSV53930298;