rs56092421

Variant names:

• chr20-388091-C-T
• rs56092421
• NM_021158.5:c.81C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_021158.5(TRIB3):​c.81C>T​(p.Thr27Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,614,090 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (31 hom.)
• Consequence: TRIB3 NM_021158.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.28
• Publications: 3 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 20-388091-C-T is Benign according to our data. Variant chr20-388091-C-T is described in ClinVar as Benign. ClinVar VariationId is 710947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.28 with no splicing effect.
• BS2: High AC in GnomAd4 at 462 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021158.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIB3	NM_021158.5	MANE Select	c.81C>T	p.Thr27Thr	synonymous	Exon 2 of 4	NP_066981.2
	TRIB3	NM_001301201.1		c.162C>T	p.Thr54Thr	synonymous	Exon 3 of 5	NP_001288130.1	J3KR25
	TRIB3	NM_001301188.1		c.81C>T	p.Thr27Thr	synonymous	Exon 2 of 4	NP_001288117.1	Q96RU7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIB3	ENST00000217233.9	TSL:1 MANE Select	c.81C>T	p.Thr27Thr	synonymous	Exon 2 of 4	ENSP00000217233.3	Q96RU7
	TRIB3	ENST00000883799.1		c.81C>T	p.Thr27Thr	synonymous	Exon 2 of 5	ENSP00000553858.1
	TRIB3	ENST00000422053.3	TSL:2	c.162C>T	p.Thr54Thr	synonymous	Exon 3 of 5	ENSP00000415416.2	J3KR25

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 463 AN: 152156 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00335 AC: 842 AN: 251302 AF XY: 0.00372

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00442 AC: 6456 AN: 1461816 Hom.: 31 Cov.: 31 AF XY: 0.00437 AC XY: 3178 AN XY: 727202

African (AFR) AF: 0.00111 AC: 37 AN: 33480

American (AMR) AF: 0.00244 AC: 109 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00276 AC: 72 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00458 AC: 395 AN: 86256

European-Finnish (FIN) AF: 0.000825 AC: 44 AN: 53360

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.00496 AC: 5513 AN: 1112008

Other (OTH) AF: 0.00450 AC: 272 AN: 60396

GnomAD4 genome AF: 0.00303 AC: 462 AN: 152274 Hom.: 2 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74450

African (AFR) AF: 0.00108 AC: 45 AN: 41564

American (AMR) AF: 0.00288 AC: 44 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00581 AC: 28 AN: 4818

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00475 AC: 323 AN: 68020

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00386 Hom.: 0

Bravo AF: 0.00309

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.042
DANN	Benign	0.49
PhyloP100		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism

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: rs56092421; hg19: chr20-368735; COSMIC: COSV53931828;