Variant rs281865108 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

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).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

HPS6
NM_024747.6 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 0.0140

Variant links:

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]

HPS6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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 12 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, Uncertain_significance=2, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS6	NM_024747.6 linkuse as main transcript	c.238dup	p.Asp80GlyfsTer96	frameshift_variant	1/1	ENST00000299238.7	NP_079023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS6	ENST00000299238.7 linkuse as main transcript	c.238dup	p.Asp80GlyfsTer96	frameshift_variant	1/1		NM_024747.6	ENSP00000299238	P1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151874

Hom.:

Cov.:

show subpopulations

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:

AN:

104412

Hom.:

AF XY:

0.0000171

AC XY:

AN XY:

58448

show subpopulations

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.:

Cov.:

AF XY:

0.0000762

AC XY:

AN XY:

669278

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:

0.0000964

Gnomad4 OTH exome

AF:

0.0000531

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151874

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74194

show subpopulations

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:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 6

Pathogenic:2Uncertain: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. -
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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2009	- -

Hermansky-Pudlak syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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. -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over