ClinVar Genomic variation as it relates to human health
NM_001128126.3(AP4S1):c.295-3C>A
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_001128126.3(AP4S1):c.295-3C>A
Variation ID: 210218 Accession: VCV000210218.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q12 14: 31080570 (GRCh38) [ NCBI UCSC ] 14: 31549776 (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 5, 2015 Feb 20, 2024 Jan 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001128126.3:c.295-3C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001254726.2:c.295-4199C>A intron variant NM_001254727.2:c.295-3C>A intron variant NM_001254728.2:c.295-3C>A intron variant NM_001254729.2:c.295-3C>A intron variant NM_007077.5:c.295-3C>A intron variant NC_000014.9:g.31080570C>A NC_000014.8:g.31549776C>A NG_031913.1:g.60465C>A - Protein change
- Other names
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- Canonical SPDI
- NC_000014.9:31080569:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- sequence_variant_affecting_splicing Sequence Ontology [SO:1000071]
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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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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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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AP4S1 | - | - |
GRCh38 GRCh37 |
130 | 162 |
Conditions - Germline
Condition
Help
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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no classifications from unflagged records (1) |
no classifications from unflagged records
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Jan 22, 2024 | RCV000192637.7 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 10, 2021 | RCV001089600.3 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 15, 2024 | RCV001383006.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 7, 2022 | RCV002221509.3 |
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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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing, research
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Spastic paraplegia 52, autosomal recessive
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Tgen's Center For Rare Childhood Disorders, Translational Genomics Research Institute (TGEN)
Accession: SCV001245070.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Observation 1:
Sex: female
Tissue: whole blood
Comment on evidence:
Human Mutation
Observation 2:
Sex: female
Tissue: whole blood
Comment on evidence:
Human Mutation
Observation 3:
Tissue: whole blood
Result:
provided evidence that the variant was affecting splicing of AP4S1; showed evidence that the proband and affected sister were expressing AP4S1 isoform 3
Observation 4:
Tissue: whole blood
Result:
showed evidence that the proband and affected sister were expressing isoform 3; unaffected parents and healthy control were expressing isoform 2
Observation 5:
Tissue: whole blood and human brain tissue
Comment on evidence:
reinforces argument that isoform 2 is a brain specific isoform and loss of it in the affected siblings results in the phenotype; there is also … (more)
reinforces argument that isoform 2 is a brain specific isoform and loss of it in the affected siblings results in the phenotype; there is also evidence for the variant resulting in aberrant splicing in general with the newly detected isoform 3, varying expression levels of isoform 1, and increased intron 4 retention (less)
Result:
showed evidence that the proband and affected sister were predominantly expressing isoform 3 with some minimal expression of isoform 1; unaffected parents predominately expressing isoform 2, some expression of isoform 1, and minimal expression of isoform 3; healthy controls showed expression of isoform 1 and 2; normal brain tissue showed expression of only isoform 2; in addition, the affected sisters, unaffected parents, healthy controls, and normal brain tissue showed varying levels of intron 4 retention with the sisters/parents showing a 2 to 3 fold higher in expression relative to the controls
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Likely pathogenic
(Nov 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia 52, autosomal recessive
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761689.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Likely pathogenic
(Apr 07, 2022)
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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: SCV002498884.2
First in ClinVar: Apr 16, 2022 Last updated: Mar 04, 2023 |
Comment:
Published RNA/functional studies demonstrate a damaging effect (McCullough et al., 2020); This variant is associated with the following publications: (PMID: 32056211, 26297806, 31660686, 17576681, 32979048)
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Pathogenic
(Jan 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001582006.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 4 of the AP4S1 gene. It does not directly change the encoded amino acid sequence of the AP4S1 protein. … (more)
This sequence change falls in intron 4 of the AP4S1 gene. It does not directly change the encoded amino acid sequence of the AP4S1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs185246578, gnomAD 0.02%). This variant has been observed in individuals with clinical features of hereditary spastic paraplegia (PMID: 26297806, 31660686). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 210218). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 01, 2020)
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no assertion criteria provided
Method: literature only
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Spastic paraplegia
Affected status: yes
Allele origin:
germline
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Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106905.1 First in ClinVar: Mar 23, 2022 Last updated: Mar 23, 2022 |
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Uncertain significance
(Mar 19, 2015)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not specified
Affected status: unknown
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000246450.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
Functional
Help
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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sequence_variant_affecting_splicing
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Tgen's Center For Rare Childhood Disorders, Translational Genomics Research Institute (TGEN)
Accession: SCV001245070.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. | Ebrahimi-Fakhari D | Brain : a journal of neurology | 2020 | PMID: 32979048 |
Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia. | McCullough CG | Human mutation | 2020 | PMID: 31660686 |
Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication. | Kodani A | eLife | 2015 | PMID: 26297806 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs185246578 ...
HelpRecord last updated Apr 15, 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.