6-166158524-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001366285.2(TBXT):c.1102G>T(p.Val368Leu) 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 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V368M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBXT NM_001366285.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0330

Genes affected

TBXT (HGNC:11515): (T-box transcription factor T) The protein encoded by this gene is an embryonic nuclear transcription factor that binds to a specific DNA element, the palindromic T-site. It binds through a region in its N-terminus, called the T-box, and effects transcription of genes required for mesoderm formation and differentiation. The protein is localized to notochord-derived cells. Variation in this gene was associated with susceptibility to neural tube defects and chordoma. A mutation in this gene was found in a family with sacral agenesis with vertebral anomalies. [provided by RefSeq, Sep 2018]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079310656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBXT	NM_001366285.2	c.1102G>T	p.Val368Leu	missense_variant	8/8	ENST00000366876.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBXT	ENST00000366876.7	c.1102G>T	p.Val368Leu	missense_variant	8/8	1	NM_001366285.2	P4
TBXT	ENST00000366871.7	c.925G>T	p.Val309Leu	missense_variant	8/8	1
TBXT	ENST00000296946.6	c.1099G>T	p.Val367Leu	missense_variant	9/9	5		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2017

The V367L variant in the T gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V367L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V367L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret V367L as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	0.13
Dann	Benign	0.57
DEOGEN2	Benign	0.18	T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.079	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.61	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.094	T;D;T
Sift4G	Benign	0.33	T;T;.
Polyphen		0.0070	B;.;.
Vest4		0.055
MutPred		0.15		Loss of catalytic residue at V367 (P = 0.0357);.;.;
MVP		0.43
MPC		0.16
ClinPred		0.27	T
GERP RS		-1.5
Varity_R		0.044
gMVP		0.15

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: rs35292451; hg19: chr6-166572012;