rs281865101

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_181507.2(HPS5):​c.879dupC​(p.Lys294GlnfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HPS5
NM_181507.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.741
Variant links:
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 12 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 11-18305438-T-TG is Pathogenic according to our data. Variant chr11-18305438-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 21822.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HPS5NM_181507.2 linkc.879dupC p.Lys294GlnfsTer6 frameshift_variant Exon 8 of 23 ENST00000349215.8 NP_852608.1 Q9UPZ3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HPS5ENST00000349215.8 linkc.879dupC p.Lys294GlnfsTer6 frameshift_variant Exon 8 of 23 1 NM_181507.2 ENSP00000265967.5 Q9UPZ3-1
HPS5ENST00000396253.7 linkc.537dupC p.Lys180GlnfsTer6 frameshift_variant Exon 7 of 22 1 ENSP00000379552.3 Q9UPZ3-2
HPS5ENST00000438420.6 linkc.537dupC p.Lys180GlnfsTer6 frameshift_variant Exon 7 of 22 1 ENSP00000399590.2 Q9UPZ3-2
HPS5ENST00000531848.1 linkc.537dupC p.Lys180GlnfsTer6 frameshift_variant Exon 7 of 11 5 ENSP00000431758.1 G3V159

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1455752
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
724652
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000271
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 5 Pathogenic:1
Sep 01, 2004
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Pathogenic:1
Mar 20, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys294Glnfs*6) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Hermansky–Pudlak syndrome (PMID: 15296495). This variant is also known as P293insC. ClinVar contains an entry for this variant (Variation ID: 21822). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs281865101; hg19: chr11-18326985; API