rs281865108

Positions:

• chr10-102065710-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024747.6(HPS6):​c.238dup​(p.Asp80GlyfsTer96) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000749 in 1,507,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L79L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: HPS6 NM_024747.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 0.0140

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 51 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-102065710-T-TG is Pathogenic according to our data. Variant chr10-102065710-T-TG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208586.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS6	NM_024747.6	c.238dup	p.Asp80GlyfsTer96	frameshift_variant	1/1	ENST00000299238.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS6	ENST00000299238.7	c.238dup	p.Asp80GlyfsTer96	frameshift_variant	1/1		NM_024747.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151874 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000192 AC: 2 AN: 104412 Hom.: 0 AF XY: 0.0000171 AC XY: 1 AN XY: 58448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000509

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000782 AC: 106 AN: 1356094 Hom.: 0 Cov.: 31 AF XY: 0.0000762 AC XY: 51 AN XY: 669278

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: 0.0000964

Gnomad4 OTH exome AF: 0.0000531

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151874 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74194

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hermansky-Pudlak syndrome 6 Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 26, 2015	The p.Asp80GlyfsX96 variant in HPS6 has been reported in 1 compound heterozygous individual with clinical features of Hermansky-Pudlak syndrome (Huizing 2009). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 80 and leads to a premature termination codon 96 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating HPS6 variants have been identified in several homozygous and compound heterozygous individuals with Hermansky-Pudlak syndrome (Zhang 2003, Huizing 2009). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 14, 2018	The HPS6 c.238dupG (p.Asp80GlyfsTer96) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Asp80GlyfsTer96 variant has been reported in one study in which it is identified in a compound heterozygous state with a missense variant in one individual diagnosed with Hermansky- Pudlak syndrome (Huizing et al. 2009). Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the limited clinical evidence and potential impact of frameshift variants, the c.238dupG (p.Asp80GlyfsTer96) 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:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 30, 2023

This sequence change creates a premature translational stop signal (p.Asp80Glyfs*96) in the HPS6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 696 amino acid(s) of the HPS6 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 19843503). ClinVar contains an entry for this variant (Variation ID: 208586). This variant disrupts a region of the HPS6 protein in which other variant(s) (p.Leu356Alafs*11) have been determined to be pathogenic (PMID: 17041891). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hermansky-Pudlak syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs281865108; hg19: chr10-103825467;