rs3816300

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001366285.2(TBXT):c.1109A>G(p.Asn370Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,606,472 control chromosomes in the GnomAD database, including 15,123 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. N370N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 2121 hom., cov: 33)

Exomes 𝑓: 0.11 ( 13002 hom. )

Consequence

TBXT
NM_001366285.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.148

Publications

26 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1012185E-4).

BP6

Variant 6-166158517-T-C is Benign according to our data. Variant chr6-166158517-T-C is described in ClinVar as [Benign]. Clinvar id is 3059077.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBXT	NM_001366285.2 link	c.1109A>G	p.Asn370Ser	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.1109A>G	p.Asn370Ser	missense_variant	Exon 8 of 8	1	NM_001366285.2	ENSP00000355841.3	J3KP65
TBXT	ENST00000366871.7 link	c.932A>G	p.Asn311Ser	missense_variant	Exon 8 of 8	1		ENSP00000355836.3	O15178-2
TBXT	ENST00000296946.6 link	c.1106A>G	p.Asn369Ser	missense_variant	Exon 9 of 9	5		ENSP00000296946.2	O15178-1

Frequencies

GnomAD3 genomes

AF:

0.146

AC:

22240

AN:

152058

Hom.:

2119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.205

Gnomad AMI

AF:

0.119

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.0836

Gnomad EAS

AF:

0.505

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.164

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0970

Gnomad OTH

AF:

0.134

GnomAD2 exomes

AF:

0.142

AC:

34849

AN:

244648

AF XY:

0.137

show subpopulations

Gnomad AFR exome

AF:

0.211

Gnomad AMR exome

AF:

0.111

Gnomad ASJ exome

AF:

0.0779

Gnomad EAS exome

AF:

0.518

Gnomad FIN exome

AF:

0.165

Gnomad NFE exome

AF:

0.0967

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.112

AC:

163149

AN:

1454296

Hom.:

13002

Cov.:

AF XY:

0.111

AC XY:

80164

AN XY:

721938

show subpopulations

African (AFR)

AF:

0.214

AC:

7136

AN:

33342

American (AMR)

AF:

0.110

AC:

4875

AN:

44474

Ashkenazi Jewish (ASJ)

AF:

0.0752

AC:

1956

AN:

25996

East Asian (EAS)

AF:

0.509

AC:

20058

AN:

39444

South Asian (SAS)

AF:

0.0972

AC:

8366

AN:

86084

European-Finnish (FIN)

AF:

0.161

AC:

8515

AN:

52898

Middle Eastern (MID)

AF:

0.119

AC:

682

AN:

5736

European-Non Finnish (NFE)

AF:

0.0940

AC:

104022

AN:

1106376

Other (OTH)

AF:

0.126

AC:

7539

AN:

59946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

8700

17399

26099

34798

43498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.146

AC:

22260

AN:

152176

Hom.:

2121

Cov.:

AF XY:

0.150

AC XY:

11194

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.205

AC:

8515

AN:

41532

American (AMR)

AF:

0.104

AC:

1595

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0836

AC:

290

AN:

3468

East Asian (EAS)

AF:

0.504

AC:

2592

AN:

5144

South Asian (SAS)

AF:

0.104

AC:

500

AN:

4822

European-Finnish (FIN)

AF:

0.164

AC:

1740

AN:

10596

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0970

AC:

6595

AN:

67996

Other (OTH)

AF:

0.138

AC:

291

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

945

1889

2834

3778

4723

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.106

Hom.:

2170

Bravo

AF:

0.150

TwinsUK

AF:

0.0917

AC:

340

ALSPAC

AF:

0.0939

AC:

362

ESP6500AA

AF:

0.202

AC:

890

ESP6500EA

AF:

0.0937

AC:

805

ExAC

AF:

0.141

AC:

17032

Asia WGS

AF:

0.283

AC:

984

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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

0.049

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.081

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.060

T;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.72

T;T;T

MetaRNN

Benign

0.00011

T;T;T

MetaSVM

Benign

-0.92

PhyloP100

0.15

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.17

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.96

T;T;T

Sift4G

Benign

0.83

T;T;.

Polyphen

0.0

B;.;.

Vest4

0.023

MPC

0.13

ClinPred

0.00082

GERP RS

-6.6

Varity_R

0.026

gMVP

0.15

Mutation Taster

=99/1

polymorphism (auto)

(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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rs3816300

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