chrX-30854311-T-C

Position:

• chrX-30854311-T-C

Variant summary

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

The NM_152787.5(TAB3):​c.1354A>G​(p.Thr452Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,097,889 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: TAB3 NM_152787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

Genes affected

TAB3 (HGNC:30681): (TGF-beta activated kinase 1 (MAP3K7) binding protein 3) The product of this gene functions in the NF-kappaB signal transduction pathway. The encoded protein, and the similar and functionally redundant protein MAP3K7IP2/TAB2, forms a ternary complex with the protein kinase MAP3K7/TAK1 and either TRAF2 or TRAF6 in response to stimulation with the pro-inflammatory cytokines TNF or IL-1. Subsequent MAP3K7/TAK1 kinase activity triggers a signaling cascade leading to activation of the NF-kappaB transcription factor. The human genome contains a related pseudogene. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

TAB3-AS2 (HGNC:40013): (TAB3 antisense RNA 2)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09184718).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAB3	NM_152787.5	c.1354A>G	p.Thr452Ala	missense_variant	6/11	ENST00000288422.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAB3	ENST00000288422.4	c.1354A>G	p.Thr452Ala	missense_variant	6/11	5	NM_152787.5	P1
TAB3-AS2	ENST00000445240.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000455 AC: 5 AN: 1097889 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 363253

Gnomad4 AFR exome AF: 0.00

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: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

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 12, 2023

The c.1354A>G (p.T452A) alteration is located in exon 6 (coding exon 2) of the TAB3 gene. This alteration results from a A to G substitution at nucleotide position 1354, causing the threonine (T) at amino acid position 452 to be replaced by an alanine (A). 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	0.064
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;T;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.55	.;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.90	L;L;L
MutationTaster	Benign	0.74	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.70	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0	B;B;P
Vest4		0.088
MutPred		0.19		Loss of glycosylation at T452 (P = 0.0047);Loss of glycosylation at T452 (P = 0.0047);Loss of glycosylation at T452 (P = 0.0047);
MVP		0.64
MPC		0.41
ClinPred		0.44	T
GERP RS		3.7
Varity_R		0.14
gMVP		0.57

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: rs1938978715; hg19: chrX-30872428;