Variant 7-139872263-GAGAAGTTAGGCCTC-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001061.7(TBXAS1):c.122_135delAGTTAGGCCTCAGA(p.Lys41fs) 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.89

Variant links:

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 links:

TBXAS1 (HGNC:):

TBXAS1 links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
TBXAS1	NM_001061.7 linkuse as main transcript	c.122_135delAGTTAGGCCTCAGA	p.Lys41fs	frameshift_variant	2/13	ENST00000448866.7	NP_001052.3	P24557-1Q53F23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBXAS1	ENST00000448866.7 linkuse as main transcript	c.122_135delAGTTAGGCCTCAGA	p.Lys41fs	frameshift_variant	2/13	1	NM_001061.7	ENSP00000402536.3		P24557-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251406

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135870

show subpopulations

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:

AN:

1461770

Hom.:

AF XY:

0.0000358

AC XY:

AN XY:

727194

show subpopulations

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.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

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

Labcorp Genetics (formerly Invitae), Labcorp

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over