ClinVar Genomic variation as it relates to human health
NM_001061.7(TBXAS1):c.1235G>A (p.Arg412Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(1); Likely pathogenic(3); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001061.7(TBXAS1):c.1235G>A (p.Arg412Gln)
Variation ID: 11889 Accession: VCV000011889.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 140015731 (GRCh38) [ NCBI UCSC ] 7: 139715531 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Aug 4, 2024 Mar 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001061.7:c.1235G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001052.3:p.Arg412Gln missense NM_001130966.5:c.1235G>A NP_001124438.2:p.Arg412Gln missense NM_001166253.3:c.1373G>A NM_001166253.4:c.1373G>A NP_001159725.2:p.Arg458Gln missense NM_001166254.4:c.1034G>A NP_001159726.1:p.Arg345Gln missense NM_001314028.4:c.1178G>A NP_001300957.1:p.Arg393Gln missense NM_001366537.3:c.1052G>A NP_001353466.1:p.Arg351Gln missense NM_030984.6:c.1235G>A NP_112246.3:p.Arg412Gln missense NC_000007.14:g.140015731G>A NC_000007.13:g.139715531G>A NG_008422.2:g.242350G>A LRG_579:g.242350G>A LRG_579t4:c.1376G>A - Protein change
- R345Q, R351Q, R458Q, R393Q, R412Q
- Other names
- R413E
- Canonical SPDI
- NC_000007.14:140015730:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00100 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00083
Exome Aggregation Consortium (ExAC) 0.00087
1000 Genomes Project 0.00100
1000 Genomes Project 30x 0.00109
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TBXAS1 | - | - |
GRCh38 GRCh37 |
264 | 319 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (2) |
no assertion criteria provided
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Jan 6, 2020 | RCV000012664.28 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Mar 25, 2024 | RCV001283757.10 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV001571663.16 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ghosal hematodiaphyseal dysplasia
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002519849.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Ghosal hematodiaphyseal dysplasia
Affected status: yes
Allele origin:
germline
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002547326.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Sex: male
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Uncertain significance
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Ghosal hematodiaphyseal dysplasia
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805950.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Likely pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004032776.9
First in ClinVar: Sep 16, 2023 Last updated: Aug 04, 2024 |
Comment:
TBXAS1: PM3:Strong, PM2:Supporting, PP4, PS3:Supporting
Number of individuals with the variant: 3
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Uncertain significance
(Oct 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001796173.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
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, … (more)
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) (less)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Ghosal hematodiaphyseal dysplasia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048100.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Abnormal bone marrow cell morphology (present)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Ghosal hematodiaphyseal dysplasia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Suma Genomics
Accession: SCV004244382.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Likely pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002278412.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Mar 01, 2008)
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no assertion criteria provided
Method: literature only
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GHOSAL HEMATODIAPHYSEAL SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032899.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 10, 2020 |
Comment on evidence:
In affected members of a consanguineous Pakistani family with Ghosal hematodiaphyseal syndrome (GHDD; 231095), Genevieve et al. (2008) detected homozygosity for a 1238G-A transition in … (more)
In affected members of a consanguineous Pakistani family with Ghosal hematodiaphyseal syndrome (GHDD; 231095), Genevieve et al. (2008) detected homozygosity for a 1238G-A transition in the TBXAS1 gene that resulted in an arg413-to-glu amino acid substitution (R413E). (less)
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Pathogenic
(Aug 07, 2020)
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no assertion criteria provided
Method: clinical testing
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Ghosal hematodiaphyseal dysplasia
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001469125.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Uncertain significance
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Ghosal hematodiaphyseal syndrome
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142376.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Dec 21, 2020)
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no assertion criteria provided
Method: clinical testing
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Ghosal hematodiaphyseal dysplasia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Allergy Immunology Laboratory, Postgraduate Institute of Medical Education and Research, Chandigarh
Accession: SCV001450722.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Comment:
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 … (more)
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. (less)
Age: 10-19 years
Sex: male
Ethnicity/Population group: North Indian
Geographic origin: India
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel TBXAS1 variants in two Indian children with Ghosal hematodiaphyseal dysplasia: A concise report. | Sudhakar M | European journal of medical genetics | 2022 | PMID: 35395429 |
A Recurrent Biallelic Pathogenic Variant in TBXAS1 Gene Causing Ghosal Hematodiaphyseal Dysplasia. | Selina A | Indian journal of pediatrics | 2021 | PMID: 33244729 |
Ghosal hematodiaphyseal dysplasia and response to corticosteroid therapy. | Joy P | American journal of medical genetics. Part A | 2021 | PMID: 33185009 |
Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. | Zhang W | Human mutation | 2018 | PMID: 29068549 |
Ghosal Type Hematodiaphyseal Dysplasia. | Jeevan A | Indian pediatrics | 2016 | PMID: 27156553 |
Thromboxane synthase mutations in an increased bone density disorder (Ghosal syndrome). | Geneviève D | Nature genetics | 2008 | PMID: 18264100 |
Identification of thromboxane A2 synthase active site residues by molecular modeling-guided site-directed mutagenesis. | Wang LH | The Journal of biological chemistry | 1996 | PMID: 8702713 |
Text-mined citations for rs199422117 ...
HelpRecord last updated Aug 04, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.