rs199422117

chr7-140015731-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3 PP5 BP4

The NM_001061.7(TBXAS1):c.1235G>A(p.Arg412Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,613,278 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R412W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (7 hom.)
• Consequence: TBXAS1 NM_001061.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:5
• Conservation: PhyloP100: 8.60

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 Uncertain_significance. Variant got 1 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 7-140015731-G-A is Pathogenic according to our data. Variant chr7-140015731-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11889.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=3, Pathogenic=1}. Variant chr7-140015731-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.029645413).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBXAS1	NM_001061.7	c.1235G>A	p.Arg412Gln	missense_variant	11/13	ENST00000448866.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBXAS1	ENST00000448866.7	c.1235G>A	p.Arg412Gln	missense_variant	11/13	1	NM_001061.7	P1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000833 AC: 208 AN: 249760 Hom.: 1 AF XY: 0.00110 AC XY: 149 AN XY: 135192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00660

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000372 AC: 543 AN: 1460948 Hom.: 7 Cov.: 32 AF XY: 0.000513 AC XY: 373 AN XY: 726802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00559

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000865 AC: 105

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ghosal hematodiaphyseal dysplasia Pathogenic:4 Uncertain:3

Likely pathogenic, no assertion criteria provided	clinical testing	Allergy Immunology Laboratory, Postgraduate Institute of Medical Education and Research, Chandigarh	Dec 21, 2020	c.1376G>A: In-silico predictions for this variant are damaging and probably damaging. Two other missense variants affecting the same codon have been previously reported with Ghosal hematodiaphyseal syndrome. The variant was present in a heterozygous state with another variant on the other allele c.125_138del; p.Lys42ThrfsTer47. Additionally it was present in homozygous state in another patient. -
Uncertain significance, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	A variant in the next codon (c.1376G>A) has been previously reported as variant of uncertain significance in consanguineous family with Ghosal hematodiaphyseal dysplasia syndrome (David Genevie`ve, 2008) and has been submitted to ClinVar as Variant of Uncertain Significance. The missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The nucleotide is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. The variant is observed in 0.0035% alleles in gnomAD Exomes with 1 individual carrying it in a homozygous state and hence it has been classified as a variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Aug 07, 2020	- -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33185009, 27156553, 18264100) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TBXAS1: PM3:Strong, PM2:Supporting, PP4, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 413 of the TBXAS1 protein (p.Arg413Gln). This variant is present in population databases (rs199422117, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Ghosal hematodiaphyseal dysplasia (PMID: 18264100, 27156553, 33185009, 33244729, 35395429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11889). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TBXAS1 function (PMID: 8702713). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Ghosal hematodiaphyseal syndrome Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001061.4:c.1238G>A in the TBXAS1 gene has an allele frequency of 0.007 in South Asian subpopulation in the gnomAD database. It has been detected in homozygous state in one consanguineous family with Ghosal hematodiaphyseal dysplasia syndrome (PMID: 18264100). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2008	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;.;D;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.030	T;T;T;T;T;T
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.7	D;D;.;.;.;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.
Polyphen		1.0	.;.;D;D;.;.
Vest4		0.95
MVP		0.86
MPC		0.60
ClinPred		0.22	T
GERP RS		4.6
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs199422117; hg19: chr7-139715531;