Genetic Variant TAB3:p.Val454Ile (chrX-30854305-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152787.5(TAB3):c.1360G>A(p.Val454Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000896 in 111,576 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V454F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Consequence

TAB3
NM_152787.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.81

Publications

0 publications found

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:

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

TAB3-AS2 links:

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ACMG classification

Classification was made for transcript

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=0.1454938).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152787.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TAB3	NM_152787.5	MANE Select	c.1360G>A	p.Val454Ile	missense	Exon 6 of 11	NP_690000.3	Q8N5C8-1
TAB3	NM_001399870.1		c.1360G>A	p.Val454Ile	missense	Exon 6 of 10	NP_001386799.1
TAB3	NM_001399872.1		c.1360G>A	p.Val454Ile	missense	Exon 6 of 10	NP_001386801.1	Q8N5C8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TAB3	ENST00000288422.4	TSL:5 MANE Select	c.1360G>A	p.Val454Ile	missense	Exon 6 of 11	ENSP00000288422.4	Q8N5C8-1
TAB3	ENST00000378930.7	TSL:1	c.1360G>A	p.Val454Ile	missense	Exon 2 of 7	ENSP00000368212.3	Q8N5C8-1
TAB3	ENST00000378933.5	TSL:1	c.1360G>A	p.Val454Ile	missense	Exon 7 of 12	ENSP00000368215.1	Q8N5C8-1

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111576

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000896

AC:

AN:

111576

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33770

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30577

American (AMR)

AF:

0.00

AC:

AN:

10540

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3534

South Asian (SAS)

AF:

0.00

AC:

AN:

2677

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53173

Other (OTH)

AF:

0.00

AC:

AN:

1498

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.083

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

M_CAP

Benign

0.0071

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.67

PhyloP100

3.8

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.25

REVEL

Benign

0.077

Sift

Benign

0.27

Sift4G

Benign

0.34

Polyphen

0.0010

Vest4

0.062

MutPred

0.30

Gain of ubiquitination at K456 (P = 0.1204)

MVP

0.53

MPC

0.32

ClinPred

0.42

GERP RS

4.8

Varity_R

0.13

gMVP

0.52

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over