12-114674749-A-T

Position:

chr12-114674749-A-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 282378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-114674749-A-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
TBX3	NM_005996.4 linkuse as main transcript	c.1126T>A	p.Ser376Thr	missense_variant	6/7	ENST00000349155.7	NP_005987.3	O15119-2A0A024RBQ4
TBX3	NM_016569.4 linkuse as main transcript	c.1186T>A	p.Ser396Thr	missense_variant	7/8		NP_057653.3	O15119-1A0A024RBL6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX3	ENST00000349155.7 linkuse as main transcript	c.1126T>A	p.Ser376Thr	missense_variant	6/7	1	NM_005996.4	ENSP00000257567.2		O15119-2
TBX3	ENST00000257566.7 linkuse as main transcript	c.1186T>A	p.Ser396Thr	missense_variant	7/8	1		ENSP00000257566.3		O15119-1

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

GnomAD3 exomes

AF:

0.00729

AC:

1567

AN:

214832

Hom.:

AF XY:

0.00554

AC XY:

654

AN XY:

117996

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 SAS exome

AF:

0.000249

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

Gnomad4 AFR exome

AF:

0.0970

Gnomad4 AMR exome

AF:

0.00681

Gnomad4 ASJ exome

AF:

0.000117

Gnomad4 EAS exome

AF:

0.000178

Gnomad4 SAS exome

AF:

0.000356

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000350

Gnomad4 OTH exome

AF:

0.00672

GnomAD4 genome

AF:

0.0279

AC:

4242

AN:

152304

Hom.:

190

Cov.:

AF XY:

0.0269

AC XY:

2006

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0949

Gnomad4 AMR

AF:

0.0129

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.0208

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2018	- -

Ulnar-mammary syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 12, 2015

- -

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

DANN

Benign

0.89

DEOGEN2

Benign

0.24

.;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

Uncertain

2.3

.;M

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

Polyphen

0.40

B;B

Vest4

0.18

MVP

0.69

MPC

0.36

ClinPred

0.011

GERP RS

1.1

Varity_R

0.076

gMVP

0.38

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