dbSNP rs147405081: TBX5:p.Val263Met (chr12-114366360-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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:9

Conservation

PhyloP100: 7.57

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

Holt-Oram syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P, PanelApp Australia, Orphanet
heart conduction disease
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

TBX5 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=0.010288835).

BP6

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

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 597 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181486.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX5	NM_181486.4	MANE Select	c.787G>A	p.Val263Met	missense	Exon 8 of 9	NP_852259.1	Q99593-1
TBX5	NM_000192.3		c.787G>A	p.Val263Met	missense	Exon 8 of 9	NP_000183.2	Q99593-1
TBX5	NM_080717.4		c.637G>A	p.Val213Met	missense	Exon 7 of 8	NP_542448.1	Q99593-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX5	ENST00000405440.7	TSL:1 MANE Select	c.787G>A	p.Val263Met	missense	Exon 8 of 9	ENSP00000384152.3	Q99593-1
TBX5	ENST00000310346.8	TSL:1	c.787G>A	p.Val263Met	missense	Exon 8 of 9	ENSP00000309913.4	Q99593-1
TBX5	ENST00000349716.9	TSL:1	c.637G>A	p.Val213Met	missense	Exon 7 of 8	ENSP00000337723.5	Q99593-3

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

GnomAD2 exomes

AF:

0.00122

AC:

307

AN:

251214

AF XY:

0.000987

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 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

African (AFR)

AF:

0.0125

AC:

419

AN:

33480

American (AMR)

AF:

0.00221

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000194

AC:

216

AN:

1112008

Other (OTH)

AF:

0.00106

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00392

AC:

597

AN:

152124

Hom.:

Cov.:

AF XY:

0.00405

AC XY:

301

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0125

AC:

519

AN:

41522

American (AMR)

AF:

0.00386

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67994

Other (OTH)

AF:

0.00237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00165

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Holt-Oram syndrome (2)

not provided (2)

Aortic valve disease 2 (1)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.8

PhyloP100

7.6

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.47

REVEL

Benign

0.27

Sift

Benign

0.40

Sift4G

Benign

0.22

Polyphen

0.99

Vest4

0.77

MVP

0.76

MPC

1.7

ClinPred

0.038

GERP RS

5.6

Varity_R

0.091

gMVP

0.43

Mutation Taster

=13/87

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over