16-30086343-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004608.4(TBX6):c.1193A>C(p.Tyr398Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TBX6
NM_004608.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.559

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25306338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TBX6	NM_004608.4 linkuse as main transcript	c.1193A>C	p.Tyr398Ser	missense_variant	9/9	ENST00000395224.7
TBX6	XM_011545926.4 linkuse as main transcript	c.1193A>C	p.Tyr398Ser	missense_variant	9/9
TBX6	XM_047434551.1 linkuse as main transcript	c.1193A>C	p.Tyr398Ser	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX6	ENST00000395224.7 linkuse as main transcript	c.1193A>C	p.Tyr398Ser	missense_variant	9/9	1	NM_004608.4	P1	O95947-1
TBX6	ENST00000279386.6 linkuse as main transcript	c.1193A>C	p.Tyr398Ser	missense_variant	8/8	1		P1	O95947-1
TBX6	ENST00000567664.5 linkuse as main transcript	c.*327A>C		3_prime_UTR_variant, NMD_transcript_variant	7/7	5			O95947-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151864

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.90e-7

AC:

AN:

1450302

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721848

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151864

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with TBX6-related conditions. This variant is present in population databases (rs758798583, gnomAD 0.004%). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 398 of the TBX6 protein (p.Tyr398Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.090

Cadd

Benign

Dann

Benign

0.86

DEOGEN2

Benign

0.092

T;T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.42

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.55

N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.42

N;N;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

D;D;.

Sift4G

Benign

0.42

T;T;T

Polyphen

0.44

B;B;.

Vest4

0.42

MutPred

0.35

Gain of glycosylation at Y398 (P = 0.0022);Gain of glycosylation at Y398 (P = 0.0022);Gain of glycosylation at Y398 (P = 0.0022);

MVP

0.86

MPC

0.42

ClinPred

0.19

GERP RS

2.8

Varity_R

0.17

gMVP

0.53

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