Genetic Variant TBX4:p.Ala314Glu (chr17-61480239-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001321120.2(TBX4):c.941C>A(p.Ala314Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. A314V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TBX4
NM_001321120.2 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19546774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX4	NM_001321120.2 link	c.941C>A	p.Ala314Glu	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>A	p.Ala314Glu	missense_variant	Exon 8 of 9		NM_001321120.2	ENSP00000495986.1		P57082-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250082

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.13

.;.;T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.29

.;.;T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.1

L;L;L;L

PhyloP100

4.6

PrimateAI

Benign

0.42

PROVEAN

Benign

0.12

N;.;N;.

REVEL

Benign

0.27

Sift

Uncertain

0.021

D;.;D;.

Sift4G

Benign

0.73

T;.;T;.

Polyphen

0.72

.;.;P;.

Vest4

0.24

MutPred

0.19

Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);

MVP

0.85

MPC

0.71

ClinPred

0.22

GERP RS

5.8

Varity_R

0.24

gMVP

0.21

Mutation Taster

=93/7

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over