rs766602179
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The ENST00000349215.8(HPS5):c.1423del(p.Leu475SerfsTer37) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,578 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
HPS5
ENST00000349215.8 frameshift
ENST00000349215.8 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.968
Genes affected
HPS5 (HGNC:17022): (HPS5 biogenesis of lysosomal organelles complex 2 subunit 2) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 6 protein and may interact with the cytoplasmic domain of integrin, alpha-3. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 5. Multiple transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-18296884-AG-A is Pathogenic according to our data. Variant chr11-18296884-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431164.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=2, Uncertain_significance=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| HPS5 | NM_181507.2 | c.1423del | p.Leu475SerfsTer37 | frameshift_variant | 12/23 | ENST00000349215.8 | NP_852608.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| HPS5 | ENST00000349215.8 | c.1423del | p.Leu475SerfsTer37 | frameshift_variant | 12/23 | 1 | NM_181507.2 | ENSP00000265967 | P1 | |
| HPS5 | ENST00000396253.7 | c.1081del | p.Leu361SerfsTer37 | frameshift_variant | 11/22 | 1 | ENSP00000379552 | |||
| HPS5 | ENST00000438420.6 | c.1081del | p.Leu361SerfsTer37 | frameshift_variant | 11/22 | 1 | ENSP00000399590 | |||
| HPS5 | ENST00000531848.1 | c.1081del | p.Leu361SerfsTer39 | frameshift_variant | 11/11 | 5 | ENSP00000431758 |
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GnomAD3 genomes 0.0000197 AC: 3AN: 152020Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000795 AC: 20AN: 251438Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135890
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461558Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727110
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GnomAD4 genome 0.0000197 AC: 3AN: 152020Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74258
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hermansky-Pudlak syndrome 5 Pathogenic:2Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 13, 2019 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 02, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | The HPS5 c.1423delC (p.Leu475SerfsTer37) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Leu475SerfsTer37 variant has been reported in two studies in which it is found in two individuals with Hermansky-Pudlak syndrome including in one in a homozygous state and in one in a heterozygous state where a second variant was not detected (Carmona-Rivera et al. 2011; Ringeisen et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00152 in the Ashkenazi Jewish population of the Genome Aggregation Database. Characterization of the heterozygous patient's fibroblasts revealed a complete absence of HPS5 protein (Carmona-Rivera et al. 2011). Based on the evidence and the potential impact of frameshift variants, the p.Leu475SerfsTer37 variant is classified as a variant of unknown significance, but suspicious for pathogenicity for Hermansky-Pudlak syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 21, 2018 | The c.1423delC variant in the HPS5 gene has been reported previously in association with Hermansky-Pudlak syndrome, in an affected individual who was homozygous for the c.1423delC variant (reported as c.1081delC) and in an affected individual who was heterozygous for the c.1423delC variant, however no second HPS5 variant was identified (Ringeisen et al., 2013; Carmona-Rivera et al., 2011). The c.1423delC variant causes a frameshift starting with codon Leucine 475, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 37 of the new reading frame, denoted p.Leu475SerfsX37. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1423delC variant is observed in 18/246198 (0.007%) alleles in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.1423delC as a likely pathogenic variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2023 | This sequence change creates a premature translational stop signal (p.Leu475Serfs*37) in the HPS5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS5 are known to be pathogenic (PMID: 12548288, 15296495, 21833017, 26785811). This variant is present in population databases (rs766602179, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 21833017, 23607980). This variant is also known as 1081delC. ClinVar contains an entry for this variant (Variation ID: 431164). For these reasons, this variant has been classified as Pathogenic. - |
Hermansky-Pudlak syndrome Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 28, 2023 | Variant summary: HPS5 c.1423delC (p.Leu475SerfsX37) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Hermansky-Pudlak Syndrome in HGMD and classified as pathogenic in ClinVar. The variant allele was found at a frequency of 8e-05 in 251438 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in HPS5 causing Hermansky-Pudlak Syndrome (8e-05 vs 0.00047), allowing no conclusion about variant significance. c.1423delC has been reported in the literature in individuals affected with Hermansky-Pudlak Syndrome (Carmona-Rivera_2011, Ringeisen_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=1), Likely Pathogenic, (n=2) and Pathogenic(n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at