Genetic Variant TBX6:p.Gly431Ser (chr16-30086245-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004608.4(TBX6):c.1291G>A(p.Gly431Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,611,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

TBX6
NM_004608.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.791

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Mayer-Rokitansky-Kuster-Hauser syndrome
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
spondylocostal dysostosis 5
Inheritance: Unknown, AR, SD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
autosomal dominant spondylocostal dysostosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital anomaly of kidney and urinary tract
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TBX6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1380476).

BS2

High AC in GnomAdExome4 at 39 Unknown,AD,SD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004608.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX6	NM_004608.4	MANE Select	c.1291G>A	p.Gly431Ser	missense	Exon 9 of 9	NP_004599.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX6	ENST00000395224.7	TSL:1 MANE Select	c.1291G>A	p.Gly431Ser	missense	Exon 9 of 9	ENSP00000378650.2	O95947-1
TBX6	ENST00000279386.6	TSL:1	c.1291G>A	p.Gly431Ser	missense	Exon 8 of 8	ENSP00000279386.2	O95947-1
TBX6	ENST00000931584.1		c.1387G>A	p.Gly463Ser	missense	Exon 8 of 8	ENSP00000601643.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152080

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000602

AC:

AN:

249162

AF XY:

0.0000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1459638

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4484

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111658

Other (OTH)

AF:

0.0000996

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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

AF:

0.0000263

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41390

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67990

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000741

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.098

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.69

PhyloP100

0.79

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.030

REVEL

Benign

0.23

Sift

Benign

0.12

Sift4G

Benign

0.29

Polyphen

0.0050

Vest4

0.22

MutPred

0.21

Gain of glycosylation at G431 (P = 0.0286)

MVP

0.77

MPC

0.21

ClinPred

0.052

GERP RS

3.7

Varity_R

0.061

gMVP

0.30

Mutation Taster

=85/15

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over