X-30854949-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_152787.5(TAB3):c.716C>T(p.Ser239Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,206,542 control chromosomes in the GnomAD database, including 3 homozygotes. There are 539 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., 61 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (3 hom. 478 hem.)
• Consequence: TAB3 NM_152787.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.78

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006741613).
• BP6: Variant X-30854949-G-A is Benign according to our data. Variant chrX-30854949-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 790384.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 61 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAB3	NM_152787.5	c.716C>T	p.Ser239Leu	missense_variant	6/11	ENST00000288422.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAB3	ENST00000288422.4	c.716C>T	p.Ser239Leu	missense_variant	6/11	5	NM_152787.5	P1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 157 AN: 111529 Hom.: 0 Cov.: 23 AF XY: 0.00181 AC XY: 61 AN XY: 33681

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000953

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000379

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00145

Gnomad OTH AF: 0.00134

GnomAD3 exomes AF: 0.00144 AC: 250 AN: 173748 Hom.: 0 AF XY: 0.00140 AC XY: 83 AN XY: 59376

Gnomad AFR exome AF: 0.000160

Gnomad AMR exome AF: 0.000188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00882

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000921

GnomAD4 exome AF: 0.00134 AC: 1469 AN: 1095013 Hom.: 3 Cov.: 31 AF XY: 0.00133 AC XY: 478 AN XY: 360633

Gnomad4 AFR exome AF: 0.0000759

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.00902

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00141 AC: 157 AN: 111529 Hom.: 0 Cov.: 23 AF XY: 0.00181 AC XY: 61 AN XY: 33681

Gnomad4 AFR AF: 0.000196

Gnomad4 AMR AF: 0.0000953

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000379

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.00145

Gnomad4 OTH AF: 0.00134

Alfa AF: 0.00104 Hom.: 49

Bravo AF: 0.000699

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.00143 AC: 173

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 28, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.0067	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.018	D;D;D
Sift4G	Uncertain	0.026	D;D;D
Polyphen		0.084	B;B;B
Vest4		0.23
MVP		0.57
MPC		0.38
ClinPred		0.041	T
GERP RS		4.9
Varity_R		0.41
gMVP		0.49

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: rs150176434; hg19: chrX-30873066;