17-61456615-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001321120.2(TBX4):c.125C>A(p.Ala42Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000404 in 1,236,164 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000040 ( 0 hom. )

Consequence

TBX4
NM_001321120.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.52

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06491071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2 linkuse as main transcript	c.125C>A	p.Ala42Asp	missense_variant	2/9	ENST00000644296.1
LOC124904042	XR_007065872.1 linkuse as main transcript	n.2088G>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1 linkuse as main transcript	c.125C>A	p.Ala42Asp	missense_variant	2/9		NM_001321120.2	A1	P57082-2
TBX4	ENST00000240335.1 linkuse as main transcript	c.125C>A	p.Ala42Asp	missense_variant	1/8	1		P4	P57082-1
TBX4	ENST00000642491.1 linkuse as main transcript	c.125C>A	p.Ala42Asp	missense_variant	1/8			A1	P57082-2
TBX4	ENST00000589003.5 linkuse as main transcript	c.-125-9C>A		splice_polypyrimidine_tract_variant, intron_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000704

AC:

AN:

42592

Hom.:

AF XY:

0.0000816

AC XY:

AN XY:

24512

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00220

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000638

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000404

AC:

AN:

1236164

Hom.:

Cov.:

AF XY:

0.00000662

AC XY:

AN XY:

604316

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000145

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.96e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.125C>A (p.A42D) alteration is located in exon 1 (coding exon 1) of the TBX4 gene. This alteration results from a C to A substitution at nucleotide position 125, causing the alanine (A) at amino acid position 42 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.0010

BayesDel_noAF

Benign

-0.24

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.91

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.065

T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.34

N;N;N;N

MutationTaster

Benign

0.97

N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.67

N;.;N;.

REVEL

Benign

0.25

Sift

Benign

0.074

T;.;T;.

Sift4G

Benign

0.097

T;.;T;.

Polyphen

0.0080

.;.;B;.

Vest4

0.46

MutPred

0.20

Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);

MVP

0.76

MPC

0.63

ClinPred

0.093

GERP RS

4.4

Varity_R

0.32

gMVP

0.55

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