ClinVar Genomic variation as it relates to human health
NM_005114.4(HS3ST1):c.-108-6848A>G
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_005114.4(HS3ST1):c.-108-6848A>G
Variation ID: 441163 Accession: VCV000441163.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p15.33 4: 11406961 (GRCh38) [ NCBI UCSC ] 4: 11408585 (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 Oct 16, 2017 Dec 24, 2022 May 11, 2014 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005114.4:c.-108-6848A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000004.12:g.11406961T>C NC_000004.11:g.11408585T>C - Protein change
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- Other names
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- Canonical SPDI
- NC_000004.12:11406960:T:C
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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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decreased transcript level variant; Sequence Ontology [ SO:0001541]Analysis of Hs3st1 knockout mice show this gene controls an anti-inflammatory pathway of the blood vessel wall. rs16881446 is intronic to HS3ST1, which occurs in a 2.6 Mb gene desert (no other polymerase II genes). Bioinformatic analyses show that the rs16881446 region has phylogenetically conserved transcription factor binding motifs. In human cells this region exhibits an open chromatin configuration that incorporates several transcription factors, including c-myc. Analysis of heterozygotic cells showed the minor allele associated with a 50% decrease in HS3ST1 hnRNA levels and undetectable levels of c-Myc incorporation into chromatin in the variant region. Combined these data indicate that the rs16881446G allele reduces the transcription of the anti-inflammatory gene, HS3ST1. [submitted by Shworak lab, George Washington University]
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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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0.26418 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.26978
1000 Genomes Project 30x 0.26359
1000 Genomes Project 0.26418
Trans-Omics for Precision Medicine (TOPMed) 0.26235
- 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
Help
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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| HS3ST1 | - | - |
GRCh38 GRCh37 |
21 | 83 | |
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
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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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| risk factor (1) |
criteria provided, single submitter
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May 11, 2014 | RCV000509372.4 |
Submissions - Germline
| Classification
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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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risk factor
(May 11, 2014)
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criteria provided, single submitter
Method: clinical testing, research, in vitro, in vivo
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Coronary artery disorder
Arteriosclerosis disorder
Severity of coronary artery disease
(more...)
(Autosomal recessive inheritance)
Affected status: no, unknown, not applicable
Allele origin:
germline,
not applicable
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Shworak lab, George Washington University
Accession: SCV000607378.4
First in ClinVar: Oct 16, 2017 Last updated: Dec 24, 2022 |
Observation 1:
Number of individuals with the variant: 990
Family history: yes
Age: 29-102 years
Sex: mixed
Ethnicity/Population group: Causasians
Geographic origin: Northern_New_England
Tissue: Leukocytes
Observation 2:
Method: Genomic evolutionary rate profiling (GERP; comparing the hg19 build to 35 other mammalian genomes)
Result:
rs16881446 is intronic to HS3ST1, which occurs in a 2.6 Mb gene desert (no other polymerase II genes). Bioinformatic analyses show that the rs16881446 region has phylogenetically conserved transcription factor binding motifs. Thus, functional effects of rs16881446 are most likely to affect HS3ST1 transcription.
Observation 3:
Tissue: HUVEC: primary human umbilical vein endothelial cells; GM12878: lymphoblastoid; h1ES: human embryonic stem cells
Method: Formaldehyde-assisted isolation of regulatory elements on HUVECs to detect open chromatin.
Result:
In human cells this region exhibits an open chromatin configuration that incorporates several transcription factors, including c-myc.
Observation 4:
Comment on evidence:
Our analyses of Hs3st1 knockout mice show this gene controls an anti-inflammatory pathway of the blood vessel wall.
Result:
Compared to wild-type mice, Hs3st1 knockout mice exhibit increase LPS-lethality due to enhanced TNF sensitivity. Anti-inflammatory effects of antithrombin are reversed in knockout mice; in wild-type mice AT treatment reduces LPS-lethality, decreases leukocyte firm adhesion to endothelial cells and dialates isolated coronary arterioles; in knockout mice AT treatment enhances LPS-lethality, increases leukocyte firm adhesion to endothelial cells and constricts isolated coronary arterioles. Thus Hs3st1 acts at the blood vessel wall to regulate antithrombin's inflammodulatory tone.
Observation 5:
Tissue: primary microvascular endothelial cells isolated from human lung
Method: ChIP for c-Myc HLMECs with genotype specific quantitation by TaqMan real-time PCR.
Result:
HLMECs are heterozygotic (rs16881446A/G). ChIP analysis of HLMEC cells showed the rs16881446G allele associated with abolished c-Myc incorporation into chromatin of the variant region. The rs16881446G allele also associated with a 50% decrease in HS3ST1 hnRNA levels.
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Germline Functional Evidence
| Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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decreased transcript level variant
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Method citation(s):
Method citation(s):
Method citation(s):
Method citation(s):
Method citation(s):
Method citation(s):
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Shworak lab, George Washington University
Accession: SCV000607378.4
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Comment:
Analysis of Hs3st1 knockout mice show this gene controls an anti-inflammatory pathway of the blood vessel wall. rs16881446 is intronic to HS3ST1, which occurs in … (more)
Analysis of Hs3st1 knockout mice show this gene controls an anti-inflammatory pathway of the blood vessel wall. rs16881446 is intronic to HS3ST1, which occurs in a 2.6 Mb gene desert (no other polymerase II genes). Bioinformatic analyses show that the rs16881446 region has phylogenetically conserved transcription factor binding motifs. In human cells this region exhibits an open chromatin configuration that incorporates several transcription factors, including c-myc. Analysis of heterozygotic cells showed the minor allele associated with a 50% decrease in HS3ST1 hnRNA levels and undetectable levels of c-Myc incorporation into chromatin in the variant region. Combined these data indicate that the rs16881446G allele reduces the transcription of the anti-inflammatory gene, HS3ST1. (less)
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Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| HS3ST1 genotype regulates antithrombin's inflammomodulatory tone and associates with atherosclerosis. | Smits NC | Matrix biology : journal of the International Society for Matrix Biology | 2017 | PMID: 28126521 |
| Assessing the function of genetic variants in candidate gene association studies. | Rebbeck TR | Nature reviews. Genetics | 2004 | PMID: 15266341 |
| https://www.researchgate.net/profile/Nicholas_Shworak/publication/314329473_Summary_AudioSlide/data/58c06e6045851567902404f2/Summary-AudioSlide.mp4 | - | - | - | - |
Text-mined citations for rs16881446 ...
HelpRecord last updated Feb 14, 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.