6-166160936-G-A

Variant summary

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

The NM_001366285.2(TBXT):c.938C>T(p.Ser313Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBXT NM_001366285.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.35

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBXT	NM_001366285.2	c.938C>T	p.Ser313Phe	missense_variant	7/8	ENST00000366876.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBXT	ENST00000366876.7	c.938C>T	p.Ser313Phe	missense_variant	7/8	1	NM_001366285.2	P4
TBXT	ENST00000366871.7	c.761C>T	p.Ser254Phe	missense_variant	7/8	1
TBXT	ENST00000296946.6	c.935C>T	p.Ser312Phe	missense_variant	8/9	5		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.935C>T (p.S312F) alteration is located in exon 8 (coding exon 7) of the T gene. This alteration results from a C to T substitution at nucleotide position 935, causing the serine (S) at amino acid position 312 to be replaced by a phenylalanine (F). 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	Benign	0.30
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Uncertain	0.37	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.0070	D;D;.
Polyphen		0.71	P;.;.
Vest4		0.76
MutPred		0.38		Loss of phosphorylation at S307 (P = 0.1115);.;.;
MVP		0.93
MPC		0.58
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.26
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143862444; hg19: chr6-166574424; COSMIC: COSV104619716; COSMIC: COSV104619716;