12-114674749-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005996.4(TBX3):c.1126T>A(p.Ser376Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00542 in 1,594,768 control chromosomes in the GnomAD database, including 368 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 190 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 178 hom. )

Consequence

TBX3
NM_005996.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.892

Publications

4 publications found

Variant links:

COSMIC-nc: COSV57470394

Genes affected

TBX3 (HGNC:11602): (T-box transcription factor 3) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This protein is a transcriptional repressor and is thought to play a role in the anterior/posterior axis of the tetrapod forelimb. Mutations in this gene cause ulnar-mammary syndrome, affecting limb, apocrine gland, tooth, hair, and genital development. Alternative splicing of this gene results in three transcript variants encoding different isoforms; however, the full length nature of one variant has not been determined. [provided by RefSeq, Jul 2008]

TBX3 Gene-Disease associations (from GenCC):

ulnar-mammary syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
heart conduction disease
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

TBX3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016809404).

BP6

Variant 12-114674749-A-T is Benign according to our data. Variant chr12-114674749-A-T is described in ClinVar as Benign. ClinVar VariationId is 282378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX3	NM_005996.4 link	c.1126T>A	p.Ser376Thr	missense_variant	Exon 6 of 7	ENST00000349155.7	NP_005987.3
TBX3	NM_016569.4 link	c.1186T>A	p.Ser396Thr	missense_variant	Exon 7 of 8		NP_057653.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX3	ENST00000349155.7 link	c.1126T>A	p.Ser376Thr	missense_variant	Exon 6 of 7	1	NM_005996.4	ENSP00000257567.2
TBX3	ENST00000257566.7 link	c.1186T>A	p.Ser396Thr	missense_variant	Exon 7 of 8	1		ENSP00000257566.3

Frequencies

GnomAD3 genomes

AF:

0.0278

AC:

4235

AN:

152186

Hom.:

192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0950

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0129

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.00729

AC:

1567

AN:

214832

AF XY:

0.00554

show subpopulations

Gnomad AFR exome

AF:

0.0987

Gnomad AMR exome

AF:

0.00575

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000586

Gnomad OTH exome

AF:

0.00329

GnomAD4 exome

AF:

0.00305

AC:

4395

AN:

1442464

Hom.:

178

Cov.:

AF XY:

0.00266

AC XY:

1904

AN XY:

717102

show subpopulations

African (AFR)

AF:

0.0970

AC:

3236

AN:

33344

American (AMR)

AF:

0.00681

AC:

291

AN:

42730

Ashkenazi Jewish (ASJ)

AF:

0.000117

AC:

AN:

25738

East Asian (EAS)

AF:

0.000178

AC:

AN:

39220

South Asian (SAS)

AF:

0.000356

AC:

AN:

84220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44514

Middle Eastern (MID)

AF:

0.00678

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000350

AC:

387

AN:

1107088

Other (OTH)

AF:

0.00672

AC:

402

AN:

59860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

287

574

862

1149

1436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<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:

0.0279

AC:

4242

AN:

152304

Hom.:

190

Cov.:

AF XY:

0.0269

AC XY:

2006

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0949

AC:

3944

AN:

41552

American (AMR)

AF:

0.0129

AC:

197

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68024

Other (OTH)

AF:

0.0208

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

199

399

598

798

997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.00841

Hom.:

Bravo

AF:

0.0320

ESP6500AA

AF:

0.0912

AC:

399

ESP6500EA

AF:

0.000700

AC:

ExAC

AF:

0.00820

AC:

991

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ulnar-mammary syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Aug 12, 2015

Eurofins Ntd Llc (ga)

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

0.092

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0

.;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.67

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

.;M

PhyloP100

0.89

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.29

Sift

Benign

0.15

T;T

Sift4G

Benign

0.17

T;T

Vest4

0.18

ClinPred

0.011

GERP RS

1.1

Varity_R

0.076

gMVP

0.38

Mutation Taster

=100/0

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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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