NM_001061.7:c.1349C>A

Variant names:

• chr7-140015845-C-A
• rs5763
• NM_001061.7:c.1349C>A

Variant summary

Our verdict is Benign. The variant received -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. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• 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
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• ghosal hematodiaphyseal dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 287493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001061.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBXAS1	NM_001061.7	MANE Select	c.1349C>A	p.Thr450Asn	missense	Exon 11 of 13	NP_001052.3	P24557-1
	TBXAS1	NM_001166253.4		c.1487C>A	p.Thr496Asn	missense	Exon 12 of 14	NP_001159725.2	P24557-3
	TBXAS1	NM_001130966.5		c.1349C>A	p.Thr450Asn	missense	Exon 15 of 17	NP_001124438.2	P24557-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBXAS1	ENST00000448866.7	TSL:1 MANE Select	c.1349C>A	p.Thr450Asn	missense	Exon 11 of 13	ENSP00000402536.3	P24557-1
	TBXAS1	ENST00000336425.10	TSL:1	c.1349C>A	p.Thr450Asn	missense	Exon 15 of 17	ENSP00000338087.7	P24557-1
	TBXAS1	ENST00000425687.5	TSL:1	c.1148C>A	p.Thr383Asn	missense	Exon 13 of 15	ENSP00000388736.1	P24557-2

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

GnomAD2 exomes AF: 0.0141 AC: 3529 AN: 250862 AF XY: 0.0145

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 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

African (AFR) AF: 0.00290 AC: 97 AN: 33478

American (AMR) AF: 0.00733 AC: 328 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 472 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00671 AC: 579 AN: 86258

European-Finnish (FIN) AF: 0.0117 AC: 619 AN: 53106

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5768

European-Non Finnish (NFE) AF: 0.0225 AC: 25049 AN: 1112006

Other (OTH) AF: 0.0167 AC: 1010 AN: 60390

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

African (AFR) AF: 0.00371 AC: 154 AN: 41546

American (AMR) AF: 0.0133 AC: 204 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4828

European-Finnish (FIN) AF: 0.00810 AC: 86 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0230 AC: 1563 AN: 68026

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.0199 Hom.: 194

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.084
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.075
Sift	Benign	0.082	T
Sift4G	Benign	0.091	T
Polyphen		0.0040	B
Vest4		0.14
MPC		0.14
ClinPred		0.0022	T
GERP RS		0.30
gMVP		0.55
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5763; hg19: chr7-139715645;