rs202193096

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_004608.4(TBX6):c.434C>T(p.Pro145Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P145A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

TBX6
NM_004608.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 6.80

Variant links:

Genes affected

TBX6 (HGNC:11605): (T-box transcription factor 6) 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. Knockout studies in mice indicate that this gene is important for specification of paraxial mesoderm structures. [provided by RefSeq, Aug 2008]

TBX6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004608.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

PP5

Variant 16-30089130-G-A is Pathogenic according to our data. Variant chr16-30089130-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188056.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TBX6	NM_004608.4 linkuse as main transcript	c.434C>T	p.Pro145Leu	missense_variant	4/9	ENST00000395224.7
TBX6	XM_011545926.4 linkuse as main transcript	c.434C>T	p.Pro145Leu	missense_variant	4/9
TBX6	XM_047434551.1 linkuse as main transcript	c.434C>T	p.Pro145Leu	missense_variant	3/8
TBX6	XR_007064904.1 linkuse as main transcript	n.557C>T		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX6	ENST00000395224.7 linkuse as main transcript	c.434C>T	p.Pro145Leu	missense_variant	4/9	1	NM_004608.4	P1	O95947-1
TBX6	ENST00000279386.6 linkuse as main transcript	c.434C>T	p.Pro145Leu	missense_variant	3/8	1		P1	O95947-1
TBX6	ENST00000553607.1 linkuse as main transcript	c.434C>T	p.Pro145Leu	missense_variant	3/5	1			O95947-2
TBX6	ENST00000567664.5 linkuse as main transcript	c.434C>T	p.Pro145Leu	missense_variant, NMD_transcript_variant	3/7	5			O95947-2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000216

AC:

AN:

250098

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135440

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00120

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000603

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000105

AC:

153

AN:

1461752

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000655

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.000619

Gnomad4 NFE exome

AF:

0.0000728

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000105

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Scoliosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Aug 01, 2019

This variant in trans with hypomorphic TBX6 allele may contribute to congenital scoliosis development -

Spondylocostal dysostosis 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 22, 2015

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 145 of the TBX6 protein (p.Pro145Leu). This variant is present in population databases (rs202193096, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with congenital scoliosis (PMID: 25564734, 31471994). ClinVar contains an entry for this variant (Variation ID: 188056). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TBX6 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TBX6 function (PMID: 28054739, 31015262). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

0.12

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;D;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.76

D;D;D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

1.3

L;L;.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-9.6

D;D;.;.

REVEL

Pathogenic

0.74

Sift

Uncertain

0.010

D;D;.;.

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.76

MVP

0.93

MPC

0.75

ClinPred

0.86

GERP RS

5.1

Varity_R

0.64

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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