ClinVar Genomic variation as it relates to human health
NM_000460.4(THPO):c.791_794del (p.Pro264fs)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000460.4(THPO):c.791_794del (p.Pro264fs)
Variation ID: 632414 Accession: VCV000632414.6
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 3q27.1 3: 184372781-184372784 (GRCh38) [ NCBI UCSC ] 3: 184090569-184090572 (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 May 27, 2019 Apr 20, 2024 Feb 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000460.4:c.791_794del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000451.1:p.Pro264fs frameshift NM_001177597.2:c.779_782del NP_001171068.1:p.Pro260fs frameshift NM_001177598.2:c.774_777del NP_001171069.1:p.Leu259fs frameshift NM_001289997.1:c.675_678del NP_001276926.1:p.Leu226fs frameshift NM_001289998.1:c.791_794del NP_001276927.1:p.Pro264fs frameshift NM_001290003.1:c.1211_1214del NP_001276932.1:p.Pro404fs frameshift NM_001290022.1:c.779_782del NP_001276951.1:p.Pro260fs frameshift NM_001290026.1:c.774_777del NP_001276955.1:p.Leu259fs frameshift NM_001290027.1:c.675_678del NP_001276956.1:p.Leu226fs frameshift NM_001290028.1:c.791_794del NP_001276957.1:p.Pro264fs frameshift NC_000003.12:g.184372782_184372785del NC_000003.11:g.184090570_184090573del NG_012136.1:g.10361_10364del LRG_580:g.10361_10364del LRG_580t1:c.791_794del LRG_580p1:p.Pro264fs - Protein change
- P404fs, P260fs, P264fs, L226fs, L259fs
- Other names
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- Canonical SPDI
- NC_000003.12:184372780:GAGGG:G
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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THPO | - | - |
GRCh38 GRCh37 |
139 | 183 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Uncertain significance (1) |
criteria provided, single submitter
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Sep 7, 2017 | RCV000779403.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2024 | RCV003718288.2 |
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
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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
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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
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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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Uncertain significance
(Sep 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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Thrombocythemia 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000916014.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The THPO c.791_794delCCTC (p.Pro264HisfsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL … (more)
The THPO c.791_794delCCTC (p.Pro264HisfsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for essential thrombocythemia. (less)
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Uncertain significance
(Jan 10, 2024)
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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: SCV004507888.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Pro264Hisfs*5) in the THPO gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Pro264Hisfs*5) in the THPO gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acid(s) of the THPO protein. This variant is present in population databases (rs760659440, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with THPO-related conditions. ClinVar contains an entry for this variant (Variation ID: 632414). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Feb 16, 2024)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847441.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Leu226ArgfsX89 variant in THPO has not been previously reported in individuals with familial thrombocytopenia but has been identified in 0.021% (253/1180012) of non-Finnish European … (more)
The p.Leu226ArgfsX89 variant in THPO has not been previously reported in individuals with familial thrombocytopenia but has been identified in 0.021% (253/1180012) of non-Finnish European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 632414). Loss-of-function variants in the THPO gene have been reported in individuals with autosomal dominant thrombocytopenia or autosomal recessive congenital amegakaryocytic thrombocytopenia. While this variant is predicted to cause a frameshift, THPO transcripts utilize two alternative reading frames in the last exon, and loss-of-function variants in this exon are frequent in the general population. Furthermore, there is moderate evidence for the association between THPO variants and familial thrombocytopenia. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: none. (less)
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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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs760659440 ...
HelpRecord last updated May 01, 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.