rs3744448

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 links:

LOC124904042 (HGNC:):

LOC124904042 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=0.0018821359).

BP6

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

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/exons	MANE	Protein	UniProt
TBX4	NM_001321120.2 linkuse as main transcript	c.17G>C	p.Gly6Ala	missense_variant	2/9	ENST00000644296.1	NP_001308049.1	P57082-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TBX4	ENST00000644296.1 linkuse as main transcript	c.17G>C	p.Gly6Ala	missense_variant	2/9		NM_001321120.2	ENSP00000495986.1	P57082-2
TBX4	ENST00000240335.1 linkuse as main transcript	c.17G>C	p.Gly6Ala	missense_variant	1/8	1		ENSP00000240335.1	P57082-1
TBX4	ENST00000642491.1 linkuse as main transcript	c.17G>C	p.Gly6Ala	missense_variant	1/8			ENSP00000495714.1	P57082-2
TBX4	ENST00000589003.5 linkuse as main transcript	c.-125-117G>C		intron_variant		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

GnomAD3 exomes

AF:

0.169

AC:

29958

AN:

177474

Hom.:

2771

AF XY:

0.167

AC XY:

15880

AN XY:

95328

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 SAS exome

AF:

0.160

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

Gnomad4 AFR exome

AF:

0.106

Gnomad4 AMR exome

AF:

0.182

Gnomad4 ASJ exome

AF:

0.134

Gnomad4 EAS exome

AF:

0.347

Gnomad4 SAS exome

AF:

0.164

Gnomad4 FIN exome

AF:

0.251

Gnomad4 NFE exome

AF:

0.145

Gnomad4 OTH exome

AF:

0.161

GnomAD4 genome

AF:

0.152

AC:

23114

AN:

152138

Hom.:

2019

Cov.:

AF XY:

0.158

AC XY:

11725

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.108

Gnomad4 AMR

AF:

0.163

Gnomad4 ASJ

AF:

0.122

Gnomad4 EAS

AF:

0.316

Gnomad4 SAS

AF:

0.162

Gnomad4 FIN

AF:

0.258

Gnomad4 NFE

AF:

0.148

Gnomad4 OTH

AF:

0.155

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 30389748) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Coxopodopatellar syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

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

Varity_R

0.14

gMVP

0.25

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

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