dbSNP rs78115331: TBX3:p.Ser376Pro (chr12-114674749-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005996.4(TBX3):c.1126T>C(p.Ser376Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S376T) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TBX3
NM_005996.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.892

Publications

4 publications found

Variant links:

COSMIC-nc: COSV57475836

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31998152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX3	NM_005996.4 link	c.1126T>C	p.Ser376Pro	missense_variant	Exon 6 of 7	ENST00000349155.7	NP_005987.3	O15119-2A0A024RBQ4
TBX3	NM_016569.4 link	c.1186T>C	p.Ser396Pro	missense_variant	Exon 7 of 8		NP_057653.3	O15119-1A0A024RBL6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX3	ENST00000349155.7 link	c.1126T>C	p.Ser376Pro	missense_variant	Exon 6 of 7	1	NM_005996.4	ENSP00000257567.2		O15119-2
TBX3	ENST00000257566.7 link	c.1186T>C	p.Ser396Pro	missense_variant	Exon 7 of 8	1		ENSP00000257566.3		O15119-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1442470

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717106

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.00

AC:

AN:

42730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25738

East Asian (EAS)

AF:

0.00

AC:

AN:

39220

South Asian (SAS)

AF:

0.00

AC:

AN:

84222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107090

Other (OTH)

AF:

0.00

AC:

AN:

59860

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

.;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.83

T;T

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.32

T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.3

.;M

PhyloP100

0.89

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.097

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.94

P;P

Vest4

0.32

MutPred

0.17

.;Loss of glycosylation at S396 (P = 0.0098);

MVP

0.79

MPC

1.2

ClinPred

0.67

GERP RS

1.1

Varity_R

0.22

gMVP

0.40

Mutation Taster

=77/23

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over