Genetic Variant TBX6:p.Arg282Gly (chr16-30086847-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004608.4(TBX6):c.844C>G(p.Arg282Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,000 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TBX6
NM_004608.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.12

Publications

6 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):

spondylocostal dysostosis 5
Inheritance: Unknown, SD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX6	NM_004608.4	MANE Select	c.844C>G	p.Arg282Gly	missense	Exon 7 of 9	NP_004599.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TBX6	ENST00000395224.7	TSL:1 MANE Select	c.844C>G	p.Arg282Gly	missense	Exon 7 of 9	ENSP00000378650.2
TBX6	ENST00000279386.6	TSL:1	c.844C>G	p.Arg282Gly	missense	Exon 6 of 8	ENSP00000279386.2
TBX6	ENST00000567664.5	TSL:5	n.*48-152C>G		intron	N/A	ENSP00000460425.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000406

AC:

AN:

246400

AF XY:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460000

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52722

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111406

Other (OTH)

AF:

0.00

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.74

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.55

MetaSVM

Uncertain

-0.039

MutationAssessor

Benign

0.81

PhyloP100

4.1

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.50

Sift

Uncertain

0.023

Sift4G

Benign

0.24

Polyphen

0.60

Vest4

0.60

MutPred

0.35

Loss of stability (P = 0.0351)

MVP

0.91

MPC

0.29

ClinPred

0.80

GERP RS

4.3

Varity_R

0.21

gMVP

0.48

Mutation Taster

=89/11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over