17-61480239-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001321120.2(TBX4):c.941C>T(p.Ala314Val) variant causes a missense change. The variant allele was found at a frequency of 0.131 in 1,613,842 control chromosomes in the GnomAD database, including 17,444 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 4427 hom., cov: 32)

Exomes 𝑓: 0.12 ( 13017 hom. )

Consequence

TBX4
NM_001321120.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.57

Publications

27 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005241424).

BP6

Variant 17-61480239-C-T is Benign according to our data. Variant chr17-61480239-C-T is described in ClinVar as Benign. ClinVar VariationId is 261035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX4	NM_001321120.2 link	c.941C>T	p.Ala314Val	missense_variant	Exon 8 of 9	ENST00000644296.1	NP_001308049.1	P57082-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX4	ENST00000644296.1 link	c.941C>T	p.Ala314Val	missense_variant	Exon 8 of 9		NM_001321120.2	ENSP00000495986.1		P57082-2

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30625

AN:

151898

Hom.:

4406

Cov.:

show subpopulations

Gnomad AFR

AF:

0.404

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.201

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.0872

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.192

GnomAD2 exomes

AF:

0.139

AC:

34792

AN:

250082

AF XY:

0.135

show subpopulations

Gnomad AFR exome

AF:

0.419

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.199

Gnomad EAS exome

AF:

0.108

Gnomad FIN exome

AF:

0.0863

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.141

GnomAD4 exome

AF:

0.124

AC:

180782

AN:

1461826

Hom.:

13017

Cov.:

AF XY:

0.124

AC XY:

89878

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.409

AC:

13690

AN:

33480

American (AMR)

AF:

0.120

AC:

5389

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.196

AC:

5118

AN:

26136

East Asian (EAS)

AF:

0.114

AC:

4507

AN:

39700

South Asian (SAS)

AF:

0.130

AC:

11175

AN:

86258

European-Finnish (FIN)

AF:

0.0877

AC:

4679

AN:

53382

Middle Eastern (MID)

AF:

0.165

AC:

950

AN:

5768

European-Non Finnish (NFE)

AF:

0.114

AC:

126513

AN:

1111988

Other (OTH)

AF:

0.145

AC:

8761

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

11092

22184

33276

44368

55460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4782

9564

14346

19128

23910

<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:

0.202

AC:

30687

AN:

152016

Hom.:

4427

Cov.:

AF XY:

0.199

AC XY:

14761

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.404

AC:

16721

AN:

41386

American (AMR)

AF:

0.162

AC:

2483

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.201

AC:

698

AN:

3472

East Asian (EAS)

AF:

0.108

AC:

559

AN:

5166

South Asian (SAS)

AF:

0.142

AC:

686

AN:

4822

European-Finnish (FIN)

AF:

0.0872

AC:

925

AN:

10606

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8049

AN:

67970

Other (OTH)

AF:

0.194

AC:

409

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1054

2107

3161

4214

5268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

302

604

906

1208

1510

<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:

0.145

Hom.:

4053

Bravo

AF:

0.215

TwinsUK

AF:

0.108

AC:

399

ALSPAC

AF:

0.116

AC:

448

ESP6500AA

AF:

0.414

AC:

1822

ESP6500EA

AF:

0.124

AC:

1070

ExAC

AF:

0.145

AC:

17594

Asia WGS

AF:

0.168

AC:

581

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Coxopodopatellar syndrome

Benign:1

Jan 13, 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

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.062

.;.;T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.38

.;.;T;T

MetaRNN

Benign

0.0052

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L;L;L

PhyloP100

4.6

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.40

N;.;N;.

REVEL

Benign

0.26

Sift

Benign

0.035

D;.;D;.

Sift4G

Benign

0.24

T;.;T;.

Polyphen

0.85

.;.;P;.

Vest4

0.17

MPC

0.59

ClinPred

0.028

GERP RS

5.8

Varity_R

0.13

gMVP

0.15

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