NM_001321120.2:c.17G>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001321120.2(TBX4):c.17G>T(p.Gly6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,572 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6A) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TBX4
NM_001321120.2 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX4	NM_001321120.2 link	c.17G>T	p.Gly6Val	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>T	p.Gly6Val	missense_variant	Exon 2 of 9		NM_001321120.2	ENSP00000495986.1	P57082-2
TBX4	ENST00000240335.1 link	c.17G>T	p.Gly6Val	missense_variant	Exon 1 of 8	1		ENSP00000240335.1	P57082-1
TBX4	ENST00000642491.1 link	c.17G>T	p.Gly6Val	missense_variant	Exon 1 of 8			ENSP00000495714.1	P57082-2
TBX4	ENST00000589003.5 link	c.-125-117G>T		intron_variant	Intron 1 of 5	3		ENSP00000467588.1	K7EPY2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000113

AC:

AN:

177474

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000369

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000137

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1416572

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700484

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32562

American (AMR)

AF:

0.0000262

AC:

AN:

38152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25252

East Asian (EAS)

AF:

0.00

AC:

AN:

37234

South Asian (SAS)

AF:

0.00

AC:

AN:

80324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

9.18e-7

AC:

AN:

1089532

Other (OTH)

AF:

0.00

AC:

AN:

58626

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

0.0052

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

.;.;T;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

.;.;T;T

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.45

T;T;T;T

MetaSVM

Uncertain

-0.038

MutationAssessor

Benign

0.69

N;N;N;N

PhyloP100

3.1

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.21

N;.;N;.

REVEL

Uncertain

0.35

Sift

Uncertain

0.0050

D;.;D;.

Sift4G

Benign

0.25

T;.;T;.

Polyphen

0.90

.;.;P;.

Vest4

0.38

MutPred

0.19

Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);

MVP

0.91

MPC

0.89

ClinPred

0.56

GERP RS

4.3

PromoterAI

-0.056

Neutral

(source)

Varity_R

0.25

gMVP

0.33

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over