20-388057-A-T

Variant names:

• chr20-388057-A-T
• NM_021158.5:c.47A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021158.5(TRIB3):​c.47A>T​(p.Lys16Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. K16R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRIB3 NM_021158.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17690197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIB3	NM_021158.5	c.47A>T	p.Lys16Met	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.47A>T	p.Lys16Met	missense_variant	Exon 2 of 4	1	NM_021158.5	ENSP00000217233.3
TRIB3	ENST00000422053.3	c.128A>T	p.Lys43Met	missense_variant	Exon 3 of 5	2		ENSP00000415416.2
TRIB3	ENST00000449710.5	c.47A>T	p.Lys16Met	missense_variant	Exon 2 of 4	5		ENSP00000391873.2
TRIB3	ENST00000615226.4	c.47A>T	p.Lys16Met	missense_variant	Exon 4 of 5	3		ENSP00000478194.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.47A>T (p.K16M) 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 47, causing the lysine (K) at amino acid position 16 to be replaced by a methionine (M). 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	0.21
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.3	.;M;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.67	.;N;N;N
REVEL	Benign	0.060
Sift	Uncertain	0.022	.;D;D;D
Sift4G	Uncertain	0.0040	D;T;T;D
Polyphen		0.74	.;P;.;.
Vest4		0.45, 0.40
MutPred		0.18		Loss of ubiquitination at K16 (P = 0.0056);Loss of ubiquitination at K16 (P = 0.0056);Loss of ubiquitination at K16 (P = 0.0056);.;
MVP		0.76
MPC		0.77
ClinPred		0.87	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-368701;