17-61456513-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting

The NM_001321120.2(TBX4):c.23C>T(p.Ser8Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,568,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S8S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

TBX4
NM_001321120.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.67

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.31151992).

BS2

High AC in GnomAd4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX4	NM_001321120.2 link	c.23C>T	p.Ser8Phe	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.23C>T	p.Ser8Phe	missense_variant	Exon 2 of 9		NM_001321120.2	ENSP00000495986.1	P57082-2
TBX4	ENST00000240335.1 link	c.23C>T	p.Ser8Phe	missense_variant	Exon 1 of 8	1		ENSP00000240335.1	P57082-1
TBX4	ENST00000642491.1 link	c.23C>T	p.Ser8Phe	missense_variant	Exon 1 of 8			ENSP00000495714.1	P57082-2
TBX4	ENST00000589003.5 link	c.-125-111C>T		intron_variant	Intron 1 of 5	3		ENSP00000467588.1	K7EPY2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1416100

Hom.:

Cov.:

AF XY:

0.0000343

AC XY:

AN XY:

700210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.0000532

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000567

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000864

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23C>T (p.S8F) alteration is located in exon 1 (coding exon 1) of the TBX4 gene. This alteration results from a C to T substitution at nucleotide position 23, causing the serine (S) at amino acid position 8 to be replaced by a phenylalanine (F). 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

0.27

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;.;T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

.;.;T;T

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.90

L;L;L;L

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.5

N;.;N;.

REVEL

Uncertain

0.39

Sift

Uncertain

0.012

D;.;D;.

Sift4G

Uncertain

0.014

D;.;D;.

Polyphen

0.97

.;.;D;.

Vest4

0.61

MutPred

0.22

Loss of phosphorylation at S8 (P = 0.0105);Loss of phosphorylation at S8 (P = 0.0105);Loss of phosphorylation at S8 (P = 0.0105);Loss of phosphorylation at S8 (P = 0.0105);

MVP

0.89

MPC

1.3

ClinPred

0.75

GERP RS

4.3

Varity_R

0.23

gMVP

0.44

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