7-139872324-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.273

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 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, Likely_benign=1, Benign=1}. Variant chr7-139872324-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBXAS1	NM_001061.7	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	c.179G>A	p.Arg60His	missense_variant	2/13	1	NM_001061.7	P1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152100 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.00173 AC XY: 235 AN XY: 135852

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.: 5 Cov.: 31 AF XY: 0.00186 AC XY: 1350 AN XY: 726948

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.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74416

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.: 0

Bravo AF: 0.00119

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00191 AC: 232

EpiCase AF: 0.00262

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	14
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	N
LIST_S2	Benign	0.70	T;.;.;T;T;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0084	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.27	T
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	T
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

Other links and lift over

dbSNP: rs6138; hg19: chr7-139572123; COSMIC: COSV105043873;