Genetic Variant TBXT:p.Val368Met (chr6-166158524-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001366285.2(TBXT):c.1102G>A(p.Val368Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,603,094 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.012 ( 45 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 37 hom. )

Consequence

TBXT
NM_001366285.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0330

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044189095).

BP6

Variant 6-166158524-C-T is Benign according to our data. Variant chr6-166158524-C-T is described in ClinVar as [Benign]. Clinvar id is 776183.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1766/152336) while in subpopulation AFR AF= 0.0409 (1701/41574). AF 95% confidence interval is 0.0393. There are 45 homozygotes in gnomad4. There are 826 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1766 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBXT	NM_001366285.2 link	c.1102G>A	p.Val368Met	missense_variant	Exon 8 of 8	ENST00000366876.7	NP_001353214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBXT	ENST00000366876.7 link	c.1102G>A	p.Val368Met	missense_variant	Exon 8 of 8	1	NM_001366285.2	ENSP00000355841.3	J3KP65
TBXT	ENST00000366871.7 link	c.925G>A	p.Val309Met	missense_variant	Exon 8 of 8	1		ENSP00000355836.3	O15178-2
TBXT	ENST00000296946.6 link	c.1099G>A	p.Val367Met	missense_variant	Exon 9 of 9	5		ENSP00000296946.2	O15178-1

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1765

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00320

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00293

AC:

711

AN:

242766

Hom.:

AF XY:

0.00219

AC XY:

289

AN XY:

132088

show subpopulations

Gnomad AFR exome

AF:

0.0426

Gnomad AMR exome

AF:

0.00111

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000198

Gnomad FIN exome

AF:

0.0000486

Gnomad NFE exome

AF:

0.000156

Gnomad OTH exome

AF:

0.000508

GnomAD4 exome

AF:

0.00125

AC:

1807

AN:

1450758

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

781

AN XY:

719468

show subpopulations

Gnomad4 AFR exome

AF:

0.0450

Gnomad4 AMR exome

AF:

0.00137

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.0000379

Gnomad4 NFE exome

AF:

0.0000870

Gnomad4 OTH exome

AF:

0.00219

GnomAD4 genome

AF:

0.0116

AC:

1766

AN:

152336

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

826

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0409

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00334

Hom.:

Bravo

AF:

0.0127

ESP6500AA

AF:

0.0341

AC:

150

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00350

AC:

424

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000238

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.058

DANN

Benign

0.16

DEOGEN2

Benign

0.071

T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.66

T;T;T

MetaRNN

Benign

0.0044

T;T;T

MetaSVM

Benign

-0.98

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.31

N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.48

T;T;T

Sift4G

Benign

0.60

T;T;.

Polyphen

0.0030

B;.;.

Vest4

0.051

MVP

0.42

MPC

0.16

ClinPred

0.000047

GERP RS

-1.5

Varity_R

0.023

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over