rs34377097

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001060.6(TBXA2R):c.179G>T(p.Arg60Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,612,836 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 4 hom. )

Consequence

TBXA2R
NM_001060.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter P:1B:1O:1

Conservation

PhyloP100: 1.15

Variant links:

Genes affected

TBXA2R (HGNC:11608): (thromboxane A2 receptor) This gene encodes a member of the G protein-coupled receptor family. The protein interacts with thromboxane A2 to induce platelet aggregation and regulate hemostasis. A mutation in this gene results in a bleeding disorder. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

TBXA2R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06575355).

BP6

Variant 19-3600456-C-A is Benign according to our data. Variant chr19-3600456-C-A is described in ClinVar as [Benign]. Clinvar id is 12712.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBXA2R	NM_001060.6 link	c.179G>T	p.Arg60Leu	missense_variant	2/3	ENST00000375190.10	NP_001051.1	P21731-3Q05C92Q0VAB0
TBXA2R	NM_201636.3 link	c.179G>T	p.Arg60Leu	missense_variant	2/4		NP_963998.2	P21731-2Q05C92Q0VAB0
TBXA2R	XM_011528214.3 link	c.179G>T	p.Arg60Leu	missense_variant	3/4		XP_011526516.1	P21731-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TBXA2R	ENST00000375190.10 link	c.179G>T	p.Arg60Leu	missense_variant	2/3	1	NM_001060.6	ENSP00000364336.4	P21731-3
TBXA2R	ENST00000589966.1 link	c.179G>T	p.Arg60Leu	missense_variant	1/2	1		ENSP00000468145.1	K7ER80
TBXA2R	ENST00000411851.3 link	c.179G>T	p.Arg60Leu	missense_variant	2/4	2		ENSP00000393333.2	P21731-2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152162

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:

0.00154

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000576

AC:

AN:

243186

Hom.:

AF XY:

0.0000451

AC XY:

AN XY:

133082

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000788

Gnomad SAS 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:

0.000142

AC:

208

AN:

1460556

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

726628

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00517

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000489

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000662

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Bleeding disorder, platelet-type, 13, susceptibility to

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
risk factor, no assertion criteria provided	literature only	OMIM	Feb 15, 1996	- -

Asthma

Pathogenic:1

Likely risk allele, no assertion criteria provided

case-control

Allergology and Ecology Laboratory, University of Burdwan

Nov 04, 2022

STRING analysis showed that TBXA2R are involved in interaction with different known and predicted Gq proteins (guanine nucleotide-binding G protein, subunits alpha, group q). Out of all Gq proteins, GNA11 acts as an activator of phospholipase C (PLC). PLC hydrolyses phosphoinositides into the two stimulatory second messengers - inositol 1,4,5-triphosphate (IP3) and diacylglycerol. IP3 enhances cytoplasmic free calcium level and diacylglycerol (DAG) activates protein kinase C (PKC). Activated protein kinase C either directly phosphorylates LTC4 synthase enzyme and inactivates it or this regulation may involve another regulatory protein which is yet to be discovered. Inactivation of LTC4 synthase leads to reduction of Leukotriene C4 (LTC4) biosynthesis in platelets. However, in the case of risk allele rs34377097 T-bearing individuals, the non-synonymous polymorphism (R60L) in TBXA2R protein inhibits the interaction between GNA11 and TBXA2R due to the change in the positive charge potentiality at the cytoplasmic domain. This is in line with Hirata et al. 1996, who demonstrated that the R60L polymorphism significantly reduces PLC activity. That leads to simultaneous inactivation of PKC which ultimately results in LTC4 synthase enzyme activation. Activation of this enzyme leads to LTA4 to LTC4 conversion which results in acute asthmatic response including broncho-constriction, tracheolar constriction and increased mucus secretion. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;.;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.035

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.81

T;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.066

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.6

M;.;M

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.2

D;.;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0060

D;.;D

Sift4G

Uncertain

0.043

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.31

MVP

0.72

MPC

1.9

ClinPred

0.82

GERP RS

4.6

Varity_R

0.62

gMVP

0.77

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