rs1056048

chr6-166166700-G-Achr6-166166700-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001366285.2(TBXT):c.363C>T(p.Ser121=) variant causes a synonymous change. The variant allele was found at a frequency of 0.212 in 1,613,756 control chromosomes in the GnomAD database, including 38,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5169 hom., cov: 33)
  • Exomes 𝑓: 0.21 (33268 hom.)
• Consequence: TBXT NM_001366285.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.79

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 6-166166700-G-A is Benign according to our data. Variant chr6-166166700-G-A is described in ClinVar as [Benign]. Clinvar id is 1302242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBXT	NM_001366285.2	c.363C>T	p.Ser121=	synonymous_variant	2/8	ENST00000366876.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBXT	ENST00000366876.7	c.363C>T	p.Ser121=	synonymous_variant	2/8	1	NM_001366285.2	P4
TBXT	ENST00000366871.7	c.363C>T	p.Ser121=	synonymous_variant	3/8	1
TBXT	ENST00000296946.6	c.363C>T	p.Ser121=	synonymous_variant	3/9	5		A1
TBXT	ENST00000461348.2	c.363C>T	p.Ser121=	synonymous_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37469 AN: 152056 Hom.: 5152 Cov.: 33

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.0419

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.257

GnomAD3 exomes AF: 0.209 AC: 52338 AN: 250998 Hom.: 6082 AF XY: 0.204 AC XY: 27761 AN XY: 135760

Gnomad AFR exome AF: 0.363

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.0328

Gnomad SAS exome AF: 0.191

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.208 AC: 304206 AN: 1461582 Hom.: 33268 Cov.: 39 AF XY: 0.206 AC XY: 150140 AN XY: 727118

Gnomad4 AFR exome AF: 0.370

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.0340

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.176

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.213

GnomAD4 genome AF: 0.247 AC: 37540 AN: 152174 Hom.: 5169 Cov.: 33 AF XY: 0.241 AC XY: 17906 AN XY: 74406

Gnomad4 AFR AF: 0.369

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.0422

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.212

Gnomad4 OTH AF: 0.258

Alfa AF: 0.210 Hom.: 1680

Bravo AF: 0.256

Asia WGS AF: 0.163 AC: 567 AN: 3478

EpiCase AF: 0.216

EpiControl AF: 0.220

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2021

- -

TBXT-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	14
Dann	Benign	0.82

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: rs1056048; hg19: chr6-166580188; COSMIC: COSV51618311;