22-39415636-C-G

Variant names:

• chr22-39415636-C-G
• NM_006116.3:c.307C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006116.3(TAB1):​c.307C>G​(p.Arg103Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TAB1 NM_006116.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

Genes affected

TAB1 (HGNC:18157): (TGF-beta activated kinase 1 (MAP3K7) binding protein 1) The protein encoded by this gene was identified as a regulator of the MAP kinase kinase kinase MAP3K7/TAK1, which is known to mediate various intracellular signaling pathways, such as those induced by TGF beta, interleukin 1, and WNT-1. This protein interacts and thus activates TAK1 kinase. It has been shown that the C-terminal portion of this protein is sufficient for binding and activation of TAK1, while a portion of the N-terminus acts as a dominant-negative inhibitor of TGF beta, suggesting that this protein may function as a mediator between TGF beta receptors and TAK1. This protein can also interact with and activate the mitogen-activated protein kinase 14 (MAPK14/p38alpha), and thus represents an alternative activation pathway, in addition to the MAPKK pathways, which contributes to the biological responses of MAPK14 to various stimuli. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAB1	NM_006116.3	c.307C>G	p.Arg103Gly	missense_variant	Exon 3 of 11	ENST00000216160.11	NP_006107.1
TAB1	NM_153497.3	c.307C>G	p.Arg103Gly	missense_variant	Exon 3 of 11		NP_705717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAB1	ENST00000216160.11	c.307C>G	p.Arg103Gly	missense_variant	Exon 3 of 11	1	NM_006116.3	ENSP00000216160.6
TAB1	ENST00000331454.3	c.307C>G	p.Arg103Gly	missense_variant	Exon 3 of 11	1		ENSP00000333049.3
TAB1	ENST00000461775.1	n.550C>G		non_coding_transcript_exon_variant	Exon 2 of 3	3
TAB1	ENST00000473613.5	n.458C>G		non_coding_transcript_exon_variant	Exon 3 of 4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.307C>G (p.R103G) alteration is located in exon 3 (coding exon 3) of the TAB1 gene. This alteration results from a C to G substitution at nucleotide position 307, causing the arginine (R) at amino acid position 103 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.0069	T
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		0.61	P;P
Vest4		0.79
MutPred		0.56		Loss of stability (P = 0.028);Loss of stability (P = 0.028);
MVP		0.65
MPC		0.82
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.51
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-39811641;