chr7-139872324-G-A

Position:

chr7-139872324-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001061.7(TBXAS1):c.179G>A(p.Arg60His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,452 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R60C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 5 hom. )

Consequence

TBXAS1
NM_001061.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.273

Variant links:

Genes affected

TBXAS1 (HGNC:11609): (thromboxane A synthase 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. However, this protein is considered a member of the cytochrome P450 superfamily on the basis of sequence similarity rather than functional similarity. This endoplasmic reticulum membrane protein catalyzes the conversion of prostglandin H2 to thromboxane A2, a potent vasoconstrictor and inducer of platelet aggregation. The enzyme plays a role in several pathophysiological processes including hemostasis, cardiovascular disease, and stroke. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

TBXAS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008380592).

BP6

Variant 7-139872324-G-A is Benign according to our data. Variant chr7-139872324-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547027.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}. Variant chr7-139872324-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBXAS1	NM_001061.7 linkuse as main transcript	c.179G>A	p.Arg60His	missense_variant	2/13	ENST00000448866.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBXAS1	ENST00000448866.7 linkuse as main transcript	c.179G>A	p.Arg60His	missense_variant	2/13	1	NM_001061.7	P1	P24557-1

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

200

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00218

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00171

AC:

430

AN:

251374

Hom.:

AF XY:

0.00173

AC XY:

235

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.00260

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00188

AC:

2753

AN:

1461234

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

1350

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00157

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000974

Gnomad4 FIN exome

AF:

0.00309

Gnomad4 NFE exome

AF:

0.00212

Gnomad4 OTH exome

AF:

0.00144

GnomAD4 genome

AF:

0.00131

AC:

200

AN:

152218

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00255

Gnomad4 NFE

AF:

0.00218

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00202

Hom.:

Bravo

AF:

0.00119

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00191

AC:

232

EpiCase

AF:

0.00262

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 20, 2023

Variant summary: TBXAS1 c.179G>A (p.Arg60His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251374 control chromosomes in the gnomAD database, including 1 homozygote. c.179G>A has been reported in the literature in an individual affected with a bleeding disorder without strong evidence of causality (e.g. Leine_2017). This report does not provide unequivocal conclusions about association of the variant with Ghosal Hematodiaphyseal Dysplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28748566). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying variant as benign (n=1) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

TBXAS1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.058

T;.;.;.;T;T;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.70

T;.;.;T;T;.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.0084

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.5

D;.;.;.;.;.;.

REVEL

Benign

0.059

Sift

Benign

0.13

T;.;.;.;.;.;.

Sift4G

Benign

0.44

T;.;.;.;.;.;.

Polyphen

0.081, 0.032

.;.;B;B;B;.;.

Vest4

0.14

MVP

0.20

MPC

0.15

ClinPred

0.020

GERP RS

1.0

gMVP

0.69

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