rs2270150

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001321120.2(TBX4):c.1449C>T(p.Val483Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,610,470 control chromosomes in the GnomAD database, including 14,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1368 hom., cov: 32)

Exomes 𝑓: 0.13 ( 12709 hom. )

Consequence

TBX4
NM_001321120.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.00300

Publications

13 publications found

Variant links:

Genes affected

TBX4 (HGNC:11603): (T-box transcription factor 4) 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 the human homolog of mouse Tbx4, which is closely linked to Tbx2 on mouse chromosome 11. Similarly this gene, like TBX2, maps to human chromosome 17. Expression studies in mouse and chicken show that Tbx4 is expressed in developing hindlimb, but not in forelimb buds, suggesting a role for this gene in regulating limb development and specification of limb identity. [provided by RefSeq, Jul 2008]

TBX4 Gene-Disease associations (from GenCC):

coxopodopatellar syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
pulmonary arterial hypertension
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive amelia
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics
heritable pulmonary arterial hypertension
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TBX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 17-61483324-C-T is Benign according to our data. Variant chr17-61483324-C-T is described in ClinVar as Benign. ClinVar VariationId is 261033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.003 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX4	NM_001321120.2 link	c.1449C>T	p.Val483Val	synonymous_variant	Exon 9 of 9	ENST00000644296.1	NP_001308049.1	P57082-2
TBX4	NM_018488.3 link	c.1446C>T	p.Val482Val	synonymous_variant	Exon 8 of 8		NP_060958.2	P57082-1
TBX4	XM_011525490.3 link	c.1638C>T	p.Val546Val	synonymous_variant	Exon 9 of 9		XP_011523792.1
TBX4	XM_011525491.3 link	c.1635C>T	p.Val545Val	synonymous_variant	Exon 9 of 9		XP_011523793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBX4	ENST00000644296.1 link	c.1449C>T	p.Val483Val	synonymous_variant	Exon 9 of 9		NM_001321120.2	ENSP00000495986.1	P57082-2
TBX4	ENST00000240335.1 link	c.1446C>T	p.Val482Val	synonymous_variant	Exon 8 of 8	1		ENSP00000240335.1	P57082-1
TBX4	ENST00000589449.5 link	n.1115C>T		non_coding_transcript_exon_variant	Exon 8 of 8	1
TBX4	ENST00000642491.1 link	c.1449C>T	p.Val483Val	synonymous_variant	Exon 8 of 8			ENSP00000495714.1	P57082-2

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

19428

AN:

152094

Hom.:

1365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.132

Gnomad AMR

AF:

0.0922

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.0193

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.117

GnomAD2 exomes

AF:

0.113

AC:

28301

AN:

250294

AF XY:

0.115

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.0648

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.0196

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.130

AC:

189627

AN:

1458258

Hom.:

12709

Cov.:

AF XY:

0.130

AC XY:

94008

AN XY:

724694

show subpopulations

African (AFR)

AF:

0.136

AC:

4550

AN:

33416

American (AMR)

AF:

0.0682

AC:

3044

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

2726

AN:

26022

East Asian (EAS)

AF:

0.0321

AC:

1273

AN:

39618

South Asian (SAS)

AF:

0.107

AC:

9191

AN:

86186

European-Finnish (FIN)

AF:

0.129

AC:

6874

AN:

53330

Middle Eastern (MID)

AF:

0.131

AC:

755

AN:

5758

European-Non Finnish (NFE)

AF:

0.139

AC:

153993

AN:

1109036

Other (OTH)

AF:

0.120

AC:

7221

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

11198

22397

33595

44794

55992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5430

10860

16290

21720

27150

<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:

0.128

AC:

19437

AN:

152212

Hom.:

1368

Cov.:

AF XY:

0.126

AC XY:

9378

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.135

AC:

5587

AN:

41520

American (AMR)

AF:

0.0921

AC:

1408

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

365

AN:

3472

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5180

South Asian (SAS)

AF:

0.104

AC:

501

AN:

4822

European-Finnish (FIN)

AF:

0.133

AC:

1407

AN:

10616

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.142

AC:

9646

AN:

67994

Other (OTH)

AF:

0.117

AC:

246

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

861

1722

2582

3443

4304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<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:

0.134

Hom.:

2875

Bravo

AF:

0.123

Asia WGS

AF:

0.0830

AC:

290

AN:

3478

EpiCase

AF:

0.139

EpiControl

AF:

0.141

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Coxopodopatellar syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

6.2

(source)

DANN

Benign

0.74

PhyloP100

0.0030

Mutation Taster

=98/2

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over