rs147405081

Positions:

chr12-114366360-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_181486.4(TBX5):c.787G>A(p.Val263Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000882 in 1,614,004 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 6 hom. )

Consequence

TBX5
NM_181486.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.57

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010288835).

BP6

Variant 12-114366360-C-T is Benign according to our data. Variant chr12-114366360-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 198693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-114366360-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00392 (597/152124) while in subpopulation AFR AF= 0.0125 (519/41522). AF 95% confidence interval is 0.0116. There are 4 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 597 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TBX5	NM_181486.4 linkuse as main transcript	c.787G>A	p.Val263Met	missense_variant	8/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3 linkuse as main transcript	c.787G>A	p.Val263Met	missense_variant	8/9		NP_000183.2
TBX5	NM_080717.4 linkuse as main transcript	c.637G>A	p.Val213Met	missense_variant	7/8		NP_542448.1
TBX5	XM_017019912.2 linkuse as main transcript	c.835G>A	p.Val279Met	missense_variant	8/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7 linkuse as main transcript	c.787G>A	p.Val263Met	missense_variant	8/9	1	NM_181486.4	ENSP00000384152	P1	Q99593-1
TBX5	ENST00000310346.8 linkuse as main transcript	c.787G>A	p.Val263Met	missense_variant	8/9	1		ENSP00000309913	P1	Q99593-1
TBX5	ENST00000349716.9 linkuse as main transcript	c.637G>A	p.Val213Met	missense_variant	7/8	1		ENSP00000337723		Q99593-3
TBX5	ENST00000526441.1 linkuse as main transcript	c.787G>A	p.Val263Met	missense_variant	7/7	1		ENSP00000433292		Q99593-2

Frequencies

GnomAD3 genomes

AF:

0.00389

AC:

591

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00387

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00122

AC:

307

AN:

251214

Hom.:

AF XY:

0.000987

AC XY:

134

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.0124

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000565

AC:

826

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000507

AC XY:

369

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0125

Gnomad4 AMR exome

AF:

0.00221

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000194

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.00392

AC:

597

AN:

152124

Hom.:

Cov.:

AF XY:

0.00405

AC XY:

301

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0125

Gnomad4 AMR

AF:

0.00386

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000710

Hom.:

Bravo

AF:

0.00425

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00128

AC:

155

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2018	Variant summary: The TBX5 c.787G>A (p.Val263Met) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Though a recent functional study demonstrated that the variant of interest could disrupts the TBX5-NuRD interaction (Waldron 2016), another study provided evidence that TBX5 activity may be extensively regulated through alternative splicing where the variant of interest would not affect isoforms lacking exon 9 (Yamak 2015). This variant was found in 403/276910 control chromosomes (with 1 homozygous occurrence), predominantly observed in the African subpopulation at a frequency of 0.012288 (295/24008). This frequency is about 2809 times the estimated maximal expected allele frequency of a pathogenic TBX5 variant (0.0000044), strong evidence that this is a benign polymorphism. The variant was reported in the literature in affected individuals, however without strong evidence for causality (Faria 2008, Bonachea 2014), i.e. no clear co-segregation could be demonstrated. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

Holt-Oram syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2020	This variant is associated with the following publications: (PMID: 18706711, 25260786) -

Aortic valve disease 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

.;T;T;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;.;D;D

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.8

.;L;L;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.47

N;N;N;N

REVEL

Benign

0.27

Sift

Benign

0.40

T;T;T;T

Sift4G

Benign

0.22

T;T;T;T

Polyphen

0.99, 0.58

.;D;D;P

Vest4

0.77

MVP

0.76

MPC

1.7

ClinPred

0.038

GERP RS

5.6

Varity_R

0.091

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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