ClinVar Genomic variation as it relates to human health
NM_022081.6(HPS4):c.834T>A (p.Asp278Glu)
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_022081.6(HPS4):c.834T>A (p.Asp278Glu)
Variation ID: 899928 Accession: VCV000899928.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 26464796 (GRCh38) [ NCBI UCSC ] 22: 26860762 (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 31, 2020 Jul 7, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022081.6:c.834T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071364.4:p.Asp278Glu missense NM_001349896.1:c.834T>A NP_001336825.1:p.Asp278Glu missense NM_001349898.2:c.834T>A NP_001336827.1:p.Asp278Glu missense NM_001349899.2:c.834T>A NP_001336828.1:p.Asp278Glu missense NM_001349900.2:c.888T>A NP_001336829.1:p.Asp296Glu missense NM_001349901.1:c.888T>A NP_001336830.1:p.Asp296Glu missense NM_001349902.1:c.834T>A NP_001336831.1:p.Asp278Glu missense NM_001349903.2:c.834T>A NP_001336832.1:p.Asp278Glu missense NM_001349904.2:c.834T>A NP_001336833.1:p.Asp278Glu missense NM_001349905.1:c.834T>A NP_001336834.1:p.Asp278Glu missense NM_152841.2:c.819T>A NP_690054.1:p.Asp273Glu missense NR_073135.1:n.1520T>A non-coding transcript variant NR_073136.2:n.1089T>A non-coding transcript variant NR_146311.2:n.1531T>A non-coding transcript variant NR_146312.1:n.1436T>A non-coding transcript variant NR_146313.2:n.1376T>A non-coding transcript variant NR_146314.1:n.1587T>A non-coding transcript variant NR_146315.2:n.1447T>A non-coding transcript variant NR_146316.2:n.1422T>A non-coding transcript variant NC_000022.11:g.26464796A>T NC_000022.10:g.26860762A>T NG_009763.2:g.24068T>A LRG_590:g.24068T>A LRG_590t1:c.834T>A LRG_590p1:p.Asp278Glu LRG_590t2:c.819T>A LRG_590p2:p.Asp273Glu - Protein change
- D296E, D278E, D273E
- Other names
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- Canonical SPDI
- NC_000022.11:26464795:A:T
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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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD) 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00033
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00033
Trans-Omics for Precision Medicine (TOPMed) 0.00034
1000 Genomes Project 0.00020
- 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
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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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
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 26, 2021 | RCV001144818.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 24, 2022 | RCV001295726.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 26, 2024 | RCV004526806.2 |
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
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
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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
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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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hermansky-Pudlak syndrome 4
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001305433.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Aug 26, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002787960.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 24, 2022)
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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: SCV001484668.3
First in ClinVar: Mar 07, 2021 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 278 of the HPS4 … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 278 of the HPS4 protein (p.Asp278Glu). This variant is present in population databases (rs139107954, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with HPS4-related conditions. ClinVar contains an entry for this variant (Variation ID: 899928). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039046.2
First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: HPS4 c.834T>A (p.Asp278Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: HPS4 c.834T>A (p.Asp278Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 228910 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in HPS4 causing Hermansky-Pudlak Syndrome (0.00033 vs 0.00052), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.834T>A in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 899928). Based on the evidence outlined above, the variant was classified as uncertain significance. (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 rs139107954 ...
HelpRecord last updated Jul 07, 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.