rs2295490

Variant names:

• chr20-388261-A-G
• rs2295490
• NM_021158.5:c.251A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-388261-A-G
• chr20-388261-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021158.5(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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2264 hom., cov: 33)
  • Exomes 𝑓: 0.17 (24591 hom.)
• Consequence: TRIB3 NM_021158.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05
• Publications: 86 publications found

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]

TRIB3 Gene-Disease associations (from GenCC):

• cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TRIB3	NM_021158.5	c.251A>G	p.Gln84Arg	missense_variant	Exon 2 of 4	ENST00000217233.9	NP_066981.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIB3	ENST00000217233.9	c.251A>G	p.Gln84Arg	missense_variant	Exon 2 of 4	1	NM_021158.5	ENSP00000217233.3

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

GnomAD2 exomes AF: 0.178 AC: 44325 AN: 248822 AF XY: 0.191

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 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

African (AFR) AF: 0.164 AC: 5483 AN: 33480

American (AMR) AF: 0.0810 AC: 3620 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 5920 AN: 26116

East Asian (EAS) AF: 0.207 AC: 8215 AN: 39700

South Asian (SAS) AF: 0.382 AC: 32964 AN: 86234

European-Finnish (FIN) AF: 0.178 AC: 9355 AN: 52462

Middle Eastern (MID) AF: 0.215 AC: 1229 AN: 5718

European-Non Finnish (NFE) AF: 0.156 AC: 173048 AN: 1111956

Other (OTH) AF: 0.188 AC: 11359 AN: 60370

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

African (AFR) AF: 0.165 AC: 6870 AN: 41560

American (AMR) AF: 0.107 AC: 1630 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 756 AN: 3464

East Asian (EAS) AF: 0.196 AC: 1013 AN: 5172

South Asian (SAS) AF: 0.373 AC: 1805 AN: 4834

European-Finnish (FIN) AF: 0.192 AC: 2042 AN: 10608

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10515 AN: 68000

Other (OTH) AF: 0.146 AC: 308 AN: 2114

Alfa AF: 0.155 Hom.: 4743

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;.;.
PhyloP100		6.1
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
Mutation Taster		=100/0	polymorphism (auto)

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