rs3744448

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.17G>C(p.Gly6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,568,454 control chromosomes in the GnomAD database, including 20,546 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 2019 hom., cov: 33)

Exomes 𝑓: 0.16 ( 18527 hom. )

Consequence

TBX4
NM_001321120.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.06

Publications

37 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:

LOC124904042 (HGNC:):

LOC124904042 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=0.0018821359).

BP6

Variant 17-61456507-G-C is Benign according to our data. Variant chr17-61456507-G-C is described in ClinVar as Benign. ClinVar VariationId is 324241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX4	NM_001321120.2 link	c.17G>C	p.Gly6Ala	missense_variant	Exon 2 of 9	ENST00000644296.1	NP_001308049.1	P57082-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBX4	ENST00000644296.1 link	c.17G>C	p.Gly6Ala	missense_variant	Exon 2 of 9		NM_001321120.2	ENSP00000495986.1	P57082-2
TBX4	ENST00000240335.1 link	c.17G>C	p.Gly6Ala	missense_variant	Exon 1 of 8	1		ENSP00000240335.1	P57082-1
TBX4	ENST00000642491.1 link	c.17G>C	p.Gly6Ala	missense_variant	Exon 1 of 8			ENSP00000495714.1	P57082-2
TBX4	ENST00000589003.5 link	c.-125-117G>C		intron_variant	Intron 1 of 5	3		ENSP00000467588.1	K7EPY2

Frequencies

GnomAD3 genomes

AF:

0.152

AC:

23087

AN:

152020

Hom.:

2011

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.150

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.122

Gnomad EAS

AF:

0.315

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.258

Gnomad MID

AF:

0.102

Gnomad NFE

AF:

0.148

Gnomad OTH

AF:

0.149

GnomAD2 exomes

AF:

0.169

AC:

29958

AN:

177474

AF XY:

0.167

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.181

Gnomad ASJ exome

AF:

0.131

Gnomad EAS exome

AF:

0.294

Gnomad FIN exome

AF:

0.254

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.163

GnomAD4 exome

AF:

0.156

AC:

220921

AN:

1416316

Hom.:

18527

Cov.:

AF XY:

0.156

AC XY:

109566

AN XY:

700350

show subpopulations

African (AFR)

AF:

0.106

AC:

3434

AN:

32544

American (AMR)

AF:

0.182

AC:

6935

AN:

38116

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

3372

AN:

25248

East Asian (EAS)

AF:

0.347

AC:

12898

AN:

37200

South Asian (SAS)

AF:

0.164

AC:

13182

AN:

80314

European-Finnish (FIN)

AF:

0.251

AC:

12375

AN:

49230

Middle Eastern (MID)

AF:

0.173

AC:

979

AN:

5652

European-Non Finnish (NFE)

AF:

0.145

AC:

158308

AN:

1089392

Other (OTH)

AF:

0.161

AC:

9438

AN:

58620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

10505

21010

31516

42021

52526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5858

11716

17574

23432

29290

<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:

0.152

AC:

23114

AN:

152138

Hom.:

2019

Cov.:

AF XY:

0.158

AC XY:

11725

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.108

AC:

4500

AN:

41564

American (AMR)

AF:

0.163

AC:

2492

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.122

AC:

422

AN:

3472

East Asian (EAS)

AF:

0.316

AC:

1615

AN:

5114

South Asian (SAS)

AF:

0.162

AC:

779

AN:

4822

European-Finnish (FIN)

AF:

0.258

AC:

2741

AN:

10606

Middle Eastern (MID)

AF:

0.106

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.148

AC:

10071

AN:

67952

Other (OTH)

AF:

0.155

AC:

326

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

996

1992

2988

3984

4980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.154

Hom.:

1509

Bravo

AF:

0.144

TwinsUK

AF:

0.151

AC:

561

ALSPAC

AF:

0.154

AC:

592

ESP6500AA

AF:

0.105

AC:

456

ESP6500EA

AF:

0.125

AC:

1074

ExAC

AF:

0.114

AC:

13024

Asia WGS

AF:

0.217

AC:

756

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 19, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30389748) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.084

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.034

.;.;T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

0.048

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

.;.;T;T

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;N;N

PhyloP100

3.1

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.10

N;.;N;.

REVEL

Uncertain

0.29

Sift

Benign

0.51

T;.;T;.

Sift4G

Benign

1.0

T;.;T;.

Polyphen

0.35

.;.;B;.

Vest4

0.084

MPC

0.48

ClinPred

0.018

GERP RS

4.3

PromoterAI

0.015

Neutral

(source)

Varity_R

0.14

gMVP

0.25

Mutation Taster

=91/9

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