20-388078-A-T

Position:

• chr20-388078-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_021158.5(TRIB3):​c.68A>T​(p.Asp23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TRIB3 NM_021158.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.769

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0958893).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIB3	NM_021158.5	c.68A>T	p.Asp23Val	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.68A>T	p.Asp23Val	missense_variant	2/4	1	NM_021158.5	ENSP00000217233.3
TRIB3	ENST00000422053.3	c.149A>T	p.Asp50Val	missense_variant	3/5	2		ENSP00000415416.2
TRIB3	ENST00000449710.5	c.68A>T	p.Asp23Val	missense_variant	2/4	5		ENSP00000391873.2
TRIB3	ENST00000615226.4	c.68A>T	p.Asp23Val	missense_variant	4/5	3		ENSP00000478194.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727200

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2024

The c.68A>T (p.D23V) alteration is located in exon 2 (coding exon 1) of the TRIB3 gene. This alteration results from a A to T substitution at nucleotide position 68, causing the aspartic acid (D) at amino acid position 23 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.39	T;T;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.096	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	2.0	.;M;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.77	.;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0060	.;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.59	.;P;.;.
Vest4		0.31, 0.28
MutPred		0.15		Gain of MoRF binding (P = 0.0128);Gain of MoRF binding (P = 0.0128);Gain of MoRF binding (P = 0.0128);.;
MVP		0.78
MPC		0.39
ClinPred		0.19	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.075
gMVP		0.54

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: rs1483093267; hg19: chr20-368722;