rs117097130

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001366285.2(TBXT):c.1016C>T(p.Ala339Val) variant causes a missense change. The variant allele was found at a frequency of 0.00614 in 1,614,114 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A339A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0047 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0063 ( 35 hom. )

Consequence

TBXT
NM_001366285.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.51

Publications

8 publications found

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 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 Submitted by: Orphanet

TBXT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068078935).

BP6

Variant 6-166160858-G-A is Benign according to our data. Variant chr6-166160858-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 445576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBXT	NM_001366285.2 link	c.1016C>T	p.Ala339Val	missense_variant	Exon 7 of 8	ENST00000366876.7	NP_001353214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBXT	ENST00000366876.7 link	c.1016C>T	p.Ala339Val	missense_variant	Exon 7 of 8	1	NM_001366285.2	ENSP00000355841.3	J3KP65
TBXT	ENST00000366871.7 link	c.839C>T	p.Ala280Val	missense_variant	Exon 7 of 8	1		ENSP00000355836.3	O15178-2
TBXT	ENST00000296946.6 link	c.1013C>T	p.Ala338Val	missense_variant	Exon 8 of 9	5		ENSP00000296946.2	O15178-1

Frequencies

GnomAD3 genomes

AF:

0.00470

AC:

715

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00686

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00503

AC:

1266

AN:

251456

AF XY:

0.00517

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00228

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0138

Gnomad NFE exome

AF:

0.00699

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00629

AC:

9200

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00621

AC XY:

4515

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.00235

AC:

105

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00440

AC:

115

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0127

AC:

678

AN:

53380

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00718

AC:

7982

AN:

1111976

Other (OTH)

AF:

0.00460

AC:

278

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

551

1101

1652

2202

2753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

298

596

894

1192

1490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00469

AC:

715

AN:

152310

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

371

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41566

American (AMR)

AF:

0.00203

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0140

AC:

149

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00686

AC:

467

AN:

68030

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00633

Hom.:

Bravo

AF:

0.00383

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00483

AC:

587

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00807

EpiControl

AF:

0.00670

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 08, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TBXT-related disorder

Benign:1

May 02, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

T;T;T

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Benign

-0.87

PhyloP100

5.5

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.2

N;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.11

T;T;T

Sift4G

Uncertain

0.052

T;T;.

Polyphen

0.0040

B;.;.

Vest4

0.73

MVP

0.84

MPC

0.17

ClinPred

0.015

GERP RS

4.0

Varity_R

0.069

gMVP

0.25

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over