NM_001366285.2:c.363C>G

Variant names:

• chr6-166166700-G-C
• rs1056048
• NM_001366285.2:c.363C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001366285.2(TBXT):​c.363C>G​(p.Ser121Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S121S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBXT NM_001366285.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.79
• Publications: 11 publications found

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]

TBXT Gene-Disease associations (from GenCC):

• chordoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBXT	NM_001366285.2	c.363C>G	p.Ser121Arg	missense_variant	Exon 2 of 8	ENST00000366876.7	NP_001353214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBXT	ENST00000366876.7	c.363C>G	p.Ser121Arg	missense_variant	Exon 2 of 8	1	NM_001366285.2	ENSP00000355841.3
TBXT	ENST00000366871.7	c.363C>G	p.Ser121Arg	missense_variant	Exon 3 of 8	1		ENSP00000355836.3
TBXT	ENST00000296946.6	c.363C>G	p.Ser121Arg	missense_variant	Exon 3 of 9	5		ENSP00000296946.2
TBXT	ENST00000461348.2	c.363C>G	p.Ser121Arg	missense_variant	Exon 3 of 6	5		ENSP00000453512.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1732

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	0.35	D
PhyloP100		3.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;.;T
Polyphen		1.0	D;.;.;.
Vest4		0.80
MutPred		0.43		Loss of glycosylation at S121 (P = 0.0305);Loss of glycosylation at S121 (P = 0.0305);Loss of glycosylation at S121 (P = 0.0305);Loss of glycosylation at S121 (P = 0.0305);
MVP		0.97
MPC		2.1
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.93
gMVP		0.61
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1056048; hg19: chr6-166580188;