Variant 10-102065523-G-GGCGGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_024747.6(HPS6):c.60_64dup(p.Leu22ArgfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000895 in 1,552,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

HPS6
NM_024747.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.96

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 Pathogenic. Variant got 14 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 15 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-102065523-G-GGCGGC is Pathogenic according to our data. Variant chr10-102065523-G-GGCGGC is described in ClinVar as [Pathogenic]. Clinvar id is 1452276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS6	NM_024747.6 linkuse as main transcript	c.60_64dup	p.Leu22ArgfsTer33	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.60_64dup	p.Leu22ArgfsTer33	frameshift_variant	1/1		NM_024747.6	ENSP00000299238	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000192

AC:

AN:

155942

Hom.:

AF XY:

0.0000114

AC XY:

AN XY:

88050

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000362

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:

0.0000291

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000935

AC:

131

AN:

1400534

Hom.:

Cov.:

AF XY:

0.0000878

AC XY:

AN XY:

694778

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000252

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000846

Gnomad4 SAS exome

AF:

0.0000374

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.0000997

Gnomad4 OTH exome

AF:

0.000189

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 24, 2023	This sequence change creates a premature translational stop signal (p.Leu22Argfs33) in the HPS6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 754 amino acid(s) of the HPS6 protein. This variant is present in population databases (rs752399257, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Hermansky‚ÄìPudlak syndrome (PMID: 27593200, 29054114, 30990103). This variant is also known as c.64_65insGCGGC. ClinVar contains an entry for this variant (Variation ID: 1452276). This variant disrupts a region of the HPS6 protein in which other variant(s) (p.Q680) 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2024	Frameshift variant predicted to result in abnormal protein length as the last 754 amino acids are replaced with 32 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 30990103, 33878481, 27593200, 29054114, 27535533, 35644009, 38091959, 32725903) -

HPS6-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2023

The HPS6 c.60_64dup5 variant is predicted to result in a frameshift and premature protein termination (p.Leu22Argfs*33). This variant has been reported in the homozygous and compound heterozygous states in individuals with Hermansky-Pudlak syndrome 6 (reported as c.65_65insGCGGC in Wei et al 2016. PubMed ID: 27593200; Okamura et al. 2017. PubMed ID: 29054114; Bastida et al. 2019. PubMed ID: 30990103). This variant is reported in 0.0036% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-103825280-G-GGCGGC). Frameshift variants in HPS6 are expected to be pathogenic. Given the evidence, we interpret c.60_64dup (p.Leu22Argfs*33) as pathogenic. -

Hermansky-Pudlak syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 27, 2023

Variant summary: HPS6 c.60_64dupGCGGC (p.Leu22ArgfsX33) results in a frameshift and premature termination codon, predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. The variant allele was found at a frequency of 1.9e-05 in 155942 control chromosomes (gnomAD). c.60_64dupGCGGC has been reported in the literature as a biallelic genotype in multiple individuals affected with Hermansky-Pudlak Syndrome (e.g. Wei_2016, Okamura_2018, Bastida_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

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