7-139872263-GAGAAGTTAGGCCTC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001061.7(TBXAS1):c.122_135del(p.Lys41ThrfsTer47) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000205 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TBXAS1 NM_001061.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.89

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-139872263-GAGAAGTTAGGCCTC-G is Pathogenic according to our data. Variant chr7-139872263-GAGAAGTTAGGCCTC-G is described in ClinVar as [Pathogenic]. Clinvar id is 992886.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBXAS1	NM_001061.7	c.122_135del	p.Lys41ThrfsTer47	frameshift_variant	2/13	ENST00000448866.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBXAS1	ENST00000448866.7	c.122_135del	p.Lys41ThrfsTer47	frameshift_variant	2/13	1	NM_001061.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251406 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461770 Hom.: 0 AF XY: 0.0000358 AC XY: 26 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ghosal hematodiaphyseal dysplasia Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Allergy Immunology Laboratory, Postgraduate Institute of Medical Education and Research, Chandigarh

Dec 21, 2020

This variant results in a frameshift and premature truncation of the protein 47 amino acids downstream to codon 42. In silico prediction# of the variant is damaging by MutationTaster2. It was present in the heterozygous state with another variant on the other allele namely c.1376G>A; p.R459Q -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 10, 2023

This sequence change creates a premature translational stop signal (p.Lys42Thrfs*47) in the TBXAS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBXAS1 are known to be pathogenic (PMID: 22735388). This variant is present in population databases (rs763326515, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Ghosal hematodiaphyseal dysplasia (PMID: 35395429). ClinVar contains an entry for this variant (Variation ID: 992886). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs763326515; hg19: chr7-139572062;