X-30831546-G-A

Position:

chrX-30831546-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_152787.5(TAB3):c.2020C>T(p.Arg674Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000918 in 1,209,238 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.000088 ( 0 hom. 28 hem. )

Consequence

TAB3
NM_152787.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.45

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23074564).

BS2

High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TAB3	NM_152787.5 linkuse as main transcript	c.2020C>T	p.Arg674Trp	missense_variant	11/11	ENST00000288422.4
TAB3	NM_001399872.1 linkuse as main transcript	c.1936C>T	p.Arg646Trp	missense_variant	10/10
TAB3	NM_001399873.1 linkuse as main transcript	c.1918C>T	p.Arg640Trp	missense_variant	10/10
TAB3	XM_047441986.1 linkuse as main transcript	c.2020C>T	p.Arg674Trp	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAB3	ENST00000288422.4 linkuse as main transcript	c.2020C>T	p.Arg674Trp	missense_variant	11/11	5	NM_152787.5	P1	Q8N5C8-1
TAB3	ENST00000378930.7 linkuse as main transcript	c.2020C>T	p.Arg674Trp	missense_variant	7/7	1		P1	Q8N5C8-1
TAB3	ENST00000378933.5 linkuse as main transcript	c.2020C>T	p.Arg674Trp	missense_variant	12/12	1		P1	Q8N5C8-1
TAB3	ENST00000378932.6 linkuse as main transcript	c.1936C>T	p.Arg646Trp	missense_variant	11/11	1			Q8N5C8-2

Frequencies

GnomAD3 genomes

AF:

0.000126

AC:

AN:

111319

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

33519

show subpopulations

Gnomad AFR

AF:

0.0000981

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000192

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000380

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000669

GnomAD3 exomes

AF:

0.0000996

AC:

AN:

180695

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

66445

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000106

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000125

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.0000884

AC:

AN:

1097868

Hom.:

Cov.:

AF XY:

0.0000771

AC XY:

AN XY:

363230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.000171

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:

0.0000998

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.000126

AC:

AN:

111370

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

33580

show subpopulations

Gnomad4 AFR

AF:

0.0000979

Gnomad4 AMR

AF:

0.000192

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000381

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000661

Bravo

AF:

0.000242

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.2020C>T (p.R674W) alteration is located in exon 11 (coding exon 7) of the TAB3 gene. This alteration results from a C to T substitution at nucleotide position 2020, causing the arginine (R) at amino acid position 674 to be replaced by a tryptophan (W). 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

0.10

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

0.97

L;L;.

MutationTaster

Benign

0.85

D;D;D;D

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0

D;D;P

Vest4

0.13

MVP

0.73

MPC

0.77

ClinPred

0.15

GERP RS

4.7

Varity_R

0.33

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over