rs5763

Positions:

• chr7-140015845-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001061.7(TBXAS1):​c.1349C>A​(p.Thr450Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,866 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 33)
  • Exomes 𝑓: 0.019 (315 hom.)
• Consequence: TBXAS1 NM_001061.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0840

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013301253).
• BP6: Variant 7-140015845-C-A is Benign according to our data. Variant chr7-140015845-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 287493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140015845-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0141 (2147/152300) while in subpopulation NFE AF= 0.023 (1563/68026). AF 95% confidence interval is 0.022. There are 22 homozygotes in gnomad4. There are 991 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBXAS1	NM_001061.7	c.1349C>A	p.Thr450Asn	missense_variant	11/13	ENST00000448866.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBXAS1	ENST00000448866.7	c.1349C>A	p.Thr450Asn	missense_variant	11/13	1	NM_001061.7	P1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2146 AN: 152182 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00372

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00810

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0211

GnomAD3 exomes AF: 0.0141 AC: 3529 AN: 250862 Hom.: 38 AF XY: 0.0145 AC XY: 1964 AN XY: 135676

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00691

Gnomad ASJ exome AF: 0.0180

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00670

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0224

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0193 AC: 28250 AN: 1461566 Hom.: 315 Cov.: 32 AF XY: 0.0191 AC XY: 13903 AN XY: 727120

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.00733

Gnomad4 ASJ exome AF: 0.0181

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00671

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0141 AC: 2147 AN: 152300 Hom.: 22 Cov.: 33 AF XY: 0.0133 AC XY: 991 AN XY: 74472

Gnomad4 AFR AF: 0.00371

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00810

Gnomad4 NFE AF: 0.0230

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0202 Hom.: 94

Bravo AF: 0.0139

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0218 AC: 84

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0207 AC: 178

ExAC AF: 0.0147 AC: 1783

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0214

EpiControl AF: 0.0217

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 03, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.6
DANN	Benign	0.55
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.81	T;T;.;T;.;T
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.98	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.23	N;N;.;.;.;.
REVEL	Benign	0.075
Sift	Benign	0.082	T;D;.;.;.;.
Sift4G	Benign	0.091	T;T;.;.;.;.
Polyphen		0.0040	.;.;B;B;.;.
Vest4		0.14
MPC		0.14
ClinPred		0.0022	T
GERP RS		0.30
gMVP		0.55

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: rs5763; hg19: chr7-139715645;