6-166158460-T-G

Variant names:

• chr6-166158460-T-G
• rs139057807
• NM_001366285.2:c.1166A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001366285.2(TBXT):​c.1166A>C​(p.His389Pro) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H389R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBXT NM_001366285.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31
• Publications: 0 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, LIMITED Submitted by: PanelApp Australia, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20402795).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366285.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBXT	NM_001366285.2	MANE Select	c.1166A>C	p.His389Pro	missense	Exon 8 of 8	NP_001353214.1	J3KP65
	TBXT	NM_001366286.2		c.1166A>C	p.His389Pro	missense	Exon 9 of 9	NP_001353215.1	J3KP65
	TBXT	NM_003181.4		c.1163A>C	p.His388Pro	missense	Exon 9 of 9	NP_003172.1	O15178-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBXT	ENST00000366876.7	TSL:1 MANE Select	c.1166A>C	p.His389Pro	missense	Exon 8 of 8	ENSP00000355841.3	J3KP65
	TBXT	ENST00000366871.7	TSL:1	c.989A>C	p.His330Pro	missense	Exon 8 of 8	ENSP00000355836.3	O15178-2
	TBXT	ENST00000296946.6	TSL:5	c.1163A>C	p.His388Pro	missense	Exon 9 of 9	ENSP00000296946.2	O15178-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.47
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.61	T
PhyloP100		3.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.17
Sift	Benign	0.21	T
Sift4G	Benign	0.23	T
Polyphen		0.0020	B
Vest4		0.36
MutPred		0.31		Gain of relative solvent accessibility (P = 0.0098)
MVP		0.82
MPC		0.25
ClinPred		0.27	T
GERP RS		3.5
Varity_R		0.16
gMVP		0.56
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs139057807; hg19: chr6-166571948;