X-30834092-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_152787.5(TAB3):c.1949T>G(p.Val650Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,209,912 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 62 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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. V650E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 62 hem.)
• Consequence: TAB3 NM_152787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018006682).
• BS2: High Hemizygotes in GnomAdExome at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAB3	NM_152787.5	c.1949T>G	p.Val650Gly	missense_variant	10/11	ENST00000288422.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAB3	ENST00000288422.4	c.1949T>G	p.Val650Gly	missense_variant	10/11	5	NM_152787.5	P1
TAB3	ENST00000378930.7	c.1949T>G	p.Val650Gly	missense_variant	6/7	1		P1
TAB3	ENST00000378933.5	c.1949T>G	p.Val650Gly	missense_variant	11/12	1		P1
TAB3	ENST00000378932.6	c.1865T>G	p.Val622Gly	missense_variant	10/11	1

Frequencies

GnomAD3 genomes AF: 0.0000537 AC: 6 AN: 111769 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33929

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 32 AN: 183234 Hom.: 0 AF XY: 0.000325 AC XY: 22 AN XY: 67682

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000894

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 122 AN: 1098088 Hom.: 0 Cov.: 30 AF XY: 0.000171 AC XY: 62 AN XY: 363446

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: 0.00111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000570

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.0000626 AC: 7 AN: 111824 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33994

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000280

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000752

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000260 Hom.: 3

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000382

EpiControl AF: 0.000356

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

Dec 28, 2023

The c.1949T>G (p.V650G) alteration is located in exon 10 (coding exon 6) of the TAB3 gene. This alteration results from a T to G substitution at nucleotide position 1949, causing the valine (V) at amino acid position 650 to be replaced by a glycine (G). 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	0.096
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.042	T;T;.
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.48	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.48	T;T;T
Polyphen		0.099	B;B;B
Vest4		0.11
MVP		0.51
MPC		0.52
ClinPred		0.056	T
GERP RS		3.5
Varity_R		0.12
gMVP		0.47

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: rs374426886; hg19: chrX-30852209;