20-391359-C-G

Variant names:

• chr20-391359-C-G
• rs368799694
• NM_021158.5:c.364C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021158.5(TRIB3):​c.364C>G​(p.Arg122Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRIB3 NM_021158.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0420
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12029013).

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.364C>G	p.Arg122Gly	missense	Exon 3 of 4	NP_066981.2
	TRIB3	NM_001301201.1		c.445C>G	p.Arg149Gly	missense	Exon 4 of 5	NP_001288130.1	J3KR25
	TRIB3	NM_001301188.1		c.364C>G	p.Arg122Gly	missense	Exon 3 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.364C>G	p.Arg122Gly	missense	Exon 3 of 4	ENSP00000217233.3	Q96RU7
	TRIB3	ENST00000883799.1		c.364C>G	p.Arg122Gly	missense	Exon 3 of 5	ENSP00000553858.1
	TRIB3	ENST00000422053.3	TSL:2	c.445C>G	p.Arg149Gly	missense	Exon 4 of 5	ENSP00000415416.2	J3KR25

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.86
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.042
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.99	N
REVEL	Benign	0.22
Sift	Benign	0.52	T
Sift4G	Benign	0.063	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.67		Loss of stability (P = 0.0257)
MVP		0.36
MPC		0.36
ClinPred		0.11	T
GERP RS		4.1
Varity_R		0.095
gMVP		0.42
Mutation Taster		=85/15	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: rs368799694; hg19: chr20-372003;