6-166160871-C-A

Variant names:

• chr6-166160871-C-A
• rs768390079
• NM_001366285.2:c.1003G>T

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.1003G>T​(p.Val335Leu) 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. 14/21 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. V335M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBXT NM_001366285.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.357
• 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=0.081762314).

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.1003G>T	p.Val335Leu	missense	Exon 7 of 8	NP_001353214.1	J3KP65
	TBXT	NM_001366286.2		c.1003G>T	p.Val335Leu	missense	Exon 8 of 9	NP_001353215.1	J3KP65
	TBXT	NM_003181.4		c.1000G>T	p.Val334Leu	missense	Exon 8 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.1003G>T	p.Val335Leu	missense	Exon 7 of 8	ENSP00000355841.3	J3KP65
	TBXT	ENST00000366871.7	TSL:1	c.826G>T	p.Val276Leu	missense	Exon 7 of 8	ENSP00000355836.3	O15178-2
	TBXT	ENST00000296946.6	TSL:5	c.1000G>T	p.Val334Leu	missense	Exon 8 of 9	ENSP00000296946.2	O15178-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.079
DANN	Benign	0.38
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.36
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.060	N
REVEL	Uncertain	0.32
Sift	Benign	0.52	T
Sift4G	Benign	0.88	T
Polyphen		0.0010	B
Vest4		0.30
MutPred		0.15		Gain of glycosylation at P333 (P = 0.0803)
MVP		0.51
MPC		0.16
ClinPred		0.14	T
GERP RS		-8.8
Varity_R		0.044
gMVP		0.19
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs768390079; hg19: chr6-166574359; COSMIC: COSV51617593; COSMIC: COSV51617593;