X-30834130-A-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.1911T>G(p.Ile637Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,097,762 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 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: 0.0000073 (0 hom. 3 hem.)
• Consequence: TAB3 NM_152787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08423731).
• BS2: High Hemizygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAB3	NM_152787.5	c.1911T>G	p.Ile637Met	missense_variant	10/11	ENST00000288422.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAB3	ENST00000288422.4	c.1911T>G	p.Ile637Met	missense_variant	10/11	5	NM_152787.5	P1
TAB3	ENST00000378930.7	c.1911T>G	p.Ile637Met	missense_variant	6/7	1		P1
TAB3	ENST00000378933.5	c.1911T>G	p.Ile637Met	missense_variant	11/12	1		P1
TAB3	ENST00000378932.6	c.1827T>G	p.Ile609Met	missense_variant	10/11	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000437 AC: 8 AN: 183043 Hom.: 0 AF XY: 0.0000296 AC XY: 2 AN XY: 67505

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1097762 Hom.: 0 Cov.: 29 AF XY: 0.00000826 AC XY: 3 AN XY: 363122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000227

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.: 23

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

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 03, 2021

The c.1911T>G (p.I637M) 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 1911, causing the isoleucine (I) at amino acid position 637 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	0.067
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.044	T;T;.
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.93	D;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.080	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.080	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.036	B;B;B
Vest4		0.16
MutPred		0.18		Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;
MVP		0.60
MPC		0.41
ClinPred		0.12	T
GERP RS		4.6
Varity_R		0.18
gMVP		0.27

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: rs751029228; hg19: chrX-30852247;