17-61456506-G-A

Position:

chr17-61456506-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001321120.2(TBX4):c.16G>A(p.Gly6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,569,902 control chromosomes in the GnomAD database, including 6 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 5 hom. )

Consequence

TBX4
NM_001321120.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.33

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=0.008429915).

BP6

Variant 17-61456506-G-A is Benign according to our data. Variant chr17-61456506-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 324240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61456506-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00128 (195/152298) while in subpopulation NFE AF= 0.00224 (152/68006). AF 95% confidence interval is 0.00195. There are 1 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 195 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX4	NM_001321120.2 linkuse as main transcript	c.16G>A	p.Gly6Ser	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.16G>A	p.Gly6Ser	missense_variant	2/9		NM_001321120.2	ENSP00000495986.1	P57082-2
TBX4	ENST00000240335.1 linkuse as main transcript	c.16G>A	p.Gly6Ser	missense_variant	1/8	1		ENSP00000240335.1	P57082-1
TBX4	ENST00000642491.1 linkuse as main transcript	c.16G>A	p.Gly6Ser	missense_variant	1/8			ENSP00000495714.1	P57082-2
TBX4	ENST00000589003.5 linkuse as main transcript	c.-125-118G>A		intron_variant		3		ENSP00000467588.1	K7EPY2

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

195

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00223

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00109

AC:

195

AN:

179220

Hom.:

AF XY:

0.00106

AC XY:

102

AN XY:

96294

show subpopulations

Gnomad AFR exome

AF:

0.000193

Gnomad AMR exome

AF:

0.000733

Gnomad ASJ exome

AF:

0.000344

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000583

Gnomad FIN exome

AF:

0.000733

Gnomad NFE exome

AF:

0.00183

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.00185

AC:

2629

AN:

1417604

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1197

AN XY:

701024

show subpopulations

Gnomad4 AFR exome

AF:

0.000215

Gnomad4 AMR exome

AF:

0.000731

Gnomad4 ASJ exome

AF:

0.000554

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000498

Gnomad4 FIN exome

AF:

0.000871

Gnomad4 NFE exome

AF:

0.00222

Gnomad4 OTH exome

AF:

0.00130

GnomAD4 genome

AF:

0.00128

AC:

195

AN:

152298

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00224

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00178

Hom.:

Bravo

AF:

0.00122

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.000700

AC:

ExAC

AF:

0.000732

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 03, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TBX4: BS2 -

TBX4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

0.090

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.035

.;.;T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.072

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.76

.;.;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0084

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.14

N;N;N;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.21

N;.;N;.

REVEL

Benign

0.16

Sift

Benign

0.20

T;.;T;.

Sift4G

Benign

0.52

T;.;T;.

Polyphen

0.034

.;.;B;.

Vest4

0.13

MVP

0.78

MPC

0.41

ClinPred

0.0094

GERP RS

4.3

Varity_R

0.085

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