12-114403859-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3PP5_Moderate

The NM_181486.4(TBX5):c.40C>A(p.Pro14Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TBX5
NM_181486.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.79

Variant links:

Genes affected

TBX5 (HGNC:11604): (T-box transcription factor 5) 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 gene is closely linked to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12. The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

TBX5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.748

PP5

Variant 12-114403859-G-T is Pathogenic according to our data. Variant chr12-114403859-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 446369.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TBX5	NM_181486.4 linkuse as main transcript	c.40C>A	p.Pro14Thr	missense_variant	2/9	ENST00000405440.7
TBX5	NM_000192.3 linkuse as main transcript	c.40C>A	p.Pro14Thr	missense_variant	2/9
TBX5	XM_017019912.2 linkuse as main transcript	c.88C>A	p.Pro30Thr	missense_variant	2/9
TBX5	NM_080717.4 linkuse as main transcript	c.-3-1939C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX5	ENST00000405440.7 linkuse as main transcript	c.40C>A	p.Pro14Thr	missense_variant	2/9	1	NM_181486.4	P1	Q99593-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249730

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135272

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

case-control;in vitro

Center for Basic Medical Research, TEDA International Cardiovascular Hospital

Jun 01, 2016

TBX5 gene acts as a transcription factor to adjust the growth and development process of embryos, especially in the heart development. In our study, we found a novel nonsynonymous mutation of TBX5 (c.40C>A, p.Pro14Thr) in the isolated ventricular septal defect. Polyphen2, SIFT and Mutation Taster were used to predict mutation, the results are highly consistent that this mutated protein is damaging and the Proline of TBX5 is highly conservative in different species. Owing to the reasons above, it is possible that this novel heterozygous missense mutation of TBX5 is highly deleterious, and it may be one of the etiological causes for the isolated VSD in the Chinese population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.31

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T;.

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

1.0

L;L;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.9

N;N;N

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.79

MutPred

0.35

Gain of catalytic residue at H12 (P = 0.007);Gain of catalytic residue at H12 (P = 0.007);Gain of catalytic residue at H12 (P = 0.007);

MVP

0.95

MPC

1.8

ClinPred

0.88

GERP RS

5.3

Varity_R

0.27

gMVP

0.62

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