ClinVar Genomic variation as it relates to human health
NM_022081.6(HPS4):c.1546C>T (p.Gln516Ter)
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(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_022081.6(HPS4):c.1546C>T (p.Gln516Ter)
Variation ID: 2412666 Accession: VCV002412666.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 26464084 (GRCh38) [ NCBI UCSC ] 22: 26860050 (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 Feb 8, 2023 Jun 17, 2024 Feb 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022081.6:c.1546C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071364.4:p.Gln516Ter nonsense NM_001349896.1:c.1546C>T NP_001336825.1:p.Gln516Ter nonsense NM_001349898.2:c.1546C>T NP_001336827.1:p.Gln516Ter nonsense NM_001349899.2:c.1546C>T NP_001336828.1:p.Gln516Ter nonsense NM_001349900.2:c.1600C>T NP_001336829.1:p.Gln534Ter nonsense NM_001349901.1:c.1600C>T NP_001336830.1:p.Gln534Ter nonsense NM_001349902.1:c.1546C>T NP_001336831.1:p.Gln516Ter nonsense NM_001349903.2:c.1546C>T NP_001336832.1:p.Gln516Ter nonsense NM_001349904.2:c.1546C>T NP_001336833.1:p.Gln516Ter nonsense NM_001349905.1:c.1546C>T NP_001336834.1:p.Gln516Ter nonsense NM_001410832.1:c.1546C>T NP_001397761.1:p.Gln516Ter nonsense NM_152841.2:c.1531C>T NP_690054.1:p.Gln511Ter nonsense NR_073135.1:n.2232C>T non-coding transcript variant NR_073136.2:n.1801C>T non-coding transcript variant NR_146311.2:n.2243C>T non-coding transcript variant NR_146312.1:n.2148C>T non-coding transcript variant NR_146313.2:n.2088C>T non-coding transcript variant NR_146314.1:n.2299C>T non-coding transcript variant NR_146315.2:n.2159C>T non-coding transcript variant NR_146316.2:n.2134C>T non-coding transcript variant NC_000022.11:g.26464084G>A NC_000022.10:g.26860050G>A NG_009763.2:g.24780C>T LRG_590:g.24780C>T LRG_590t1:c.1546C>T LRG_590p1:p.Gln516Ter LRG_590t2:c.1531C>T LRG_590p2:p.Gln511Ter - Protein change
- Q511*, Q516*, Q534*
- Other names
- NR_146316.2:n.2134C>T
- Canonical SPDI
- NC_000022.11:26464083: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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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
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
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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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HPS4 | - | - |
GRCh38 GRCh37 |
816 | 847 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 17, 2024 | RCV002789957.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 15, 2023 | RCV003108234.5 |
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
(Jan 24, 2023)
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criteria provided, single submitter
Method: curation
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Hermansky-Pudlak syndrome 4
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761106.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Gln516Ter variant in HPS4 has been reported in 1 individual, in the compound heterozygous state, with Hermansky-Pudlak syndrome 4 (PMID: 31898847) and has been … (more)
The p.Gln516Ter variant in HPS4 has been reported in 1 individual, in the compound heterozygous state, with Hermansky-Pudlak syndrome 4 (PMID: 31898847) and has been identified in 0.002% (2/113762) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs372833027). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 516, which is predicted to lead to a truncated or absent protein. Loss of function of the HPS4 gene is strongly associated to autosomal recessive Hermansky-Pudlak syndrome 4. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_strong, PM2_supporting (Richards 2015). (less)
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Pathogenic
(Jul 15, 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: SCV003782828.3
First in ClinVar: Feb 13, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln516*) in the HPS4 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln516*) in the HPS4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS4 are known to be pathogenic (PMID: 12664304). This variant is present in population databases (rs372833027, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Hermansky–Pudlak syndrome (PMID: 31898847). ClinVar contains an entry for this variant (Variation ID: 2412666). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hermansky-Pudlak syndrome 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005059733.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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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
HelpText-mined citations for this variant ...
HelpRecord last updated Jun 23, 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.