rs281865112
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_024747.6(HPS6):c.1234C>T(p.Gln412Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000434 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
HPS6
NM_024747.6 stop_gained
NM_024747.6 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.84
Genes affected
HPS6 (HGNC:18817): (HPS6 biogenesis of lysosomal organelles complex 2 subunit 3) This intronless 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 5 protein. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 6. [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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 10-102066708-C-T is Pathogenic according to our data. Variant chr10-102066708-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30677.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-102066708-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HPS6 | NM_024747.6 | c.1234C>T | p.Gln412Ter | stop_gained | 1/1 | ENST00000299238.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HPS6 | ENST00000299238.7 | c.1234C>T | p.Gln412Ter | stop_gained | 1/1 | NM_024747.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250062Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135532
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461572Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 727094
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hermansky-Pudlak syndrome 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2009 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 08, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HPS6 protein in which other variant(s) (p.Gln680*) have been determined to be pathogenic (PMID: 27225848). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 30677). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 19843503). This variant is present in population databases (rs281865112, gnomAD 0.0008%). This sequence change creates a premature translational stop signal (p.Gln412*) in the HPS6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 364 amino acid(s) of the HPS6 protein. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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