rs5762

Variant names:

• chr7-140015766-C-T
• rs5762
• NM_001061.7:c.1270C>T

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.1270C>T​(p.Arg424Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000451 in 1,613,452 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R424H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (3 hom.)
• Consequence: TBXAS1 NM_001061.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.811
• Publications: 13 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=0.009269536).
• BP6: Variant 7-140015766-C-T is Benign according to our data. Variant chr7-140015766-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1653640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00194 (295/152346) while in subpopulation AFR AF = 0.00628 (261/41572). AF 95% confidence interval is 0.00565. There are 1 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.1270C>T	p.Arg424Cys	missense	Exon 11 of 13	NP_001052.3	P24557-1
	TBXAS1	NM_001166253.4		c.1408C>T	p.Arg470Cys	missense	Exon 12 of 14	NP_001159725.2	P24557-3
	TBXAS1	NM_001130966.5		c.1270C>T	p.Arg424Cys	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.1270C>T	p.Arg424Cys	missense	Exon 11 of 13	ENSP00000402536.3	P24557-1
	TBXAS1	ENST00000336425.10	TSL:1	c.1270C>T	p.Arg424Cys	missense	Exon 15 of 17	ENSP00000338087.7	P24557-1
	TBXAS1	ENST00000425687.5	TSL:1	c.1069C>T	p.Arg357Cys	missense	Exon 13 of 15	ENSP00000388736.1	P24557-2

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000664 AC: 166 AN: 250186 AF XY: 0.000539

Gnomad AFR exome AF: 0.00622

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000296 AC: 432 AN: 1461106 Hom.: 3 Cov.: 32 AF XY: 0.000275 AC XY: 200 AN XY: 726900

African (AFR) AF: 0.00666 AC: 223 AN: 33476

American (AMR) AF: 0.000559 AC: 25 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52670

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5756

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111996

Other (OTH) AF: 0.000878 AC: 53 AN: 60390

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74492

African (AFR) AF: 0.00628 AC: 261 AN: 41572

American (AMR) AF: 0.000915 AC: 14 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68042

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000728 Hom.: 0

Bravo AF: 0.00231

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000782 AC: 95

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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)
-	-	1	TBXAS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.82	T
PhyloP100		0.81
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.22
Sift	Benign	0.17	T
Sift4G	Benign	0.13	T
Polyphen		0.17	B
Vest4		0.23
MVP		0.75
MPC		0.16
ClinPred		0.0087	T
GERP RS		3.6
gMVP		0.74
Mutation Taster		=91/9	polymorphism

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: rs5762; hg19: chr7-139715566; COSMIC: COSV54956110;