10-102065523-G-GGCGGC

Variant names:

• chr10-102065523-G-GGCGGC
• rs752399257
• NM_024747.6:c.60_64dupGCGGC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_024747.6(HPS6):​c.60_64dupGCGGC​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.96

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 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 14 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 rank	MANE	Protein	UniProt
HPS6	NM_024747.6	c.60_64dupGCGGC	p.Leu22ArgfsTer33	frameshift_variant	Exon 1 of 1	ENST00000299238.7	NP_079023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS6	ENST00000299238.7	c.60_64dupGCGGC	p.Leu22ArgfsTer33	frameshift_variant	Exon 1 of 1	6	NM_024747.6	ENSP00000299238.5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152148 Hom.: 0 Cov.: 33

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: 3 AN: 155942 Hom.: 0 AF XY: 0.0000114 AC XY: 1 AN XY: 88050

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.: 0 Cov.: 31 AF XY: 0.0000878 AC XY: 61 AN XY: 694778

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: 8 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74450

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

Submissions by phenotype

not provided Pathogenic:2

Jan 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 27, 2025

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.Leu22Argfs*33) 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–Pudlak 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. -

HPS6-related disorder Pathogenic:1

Jul 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 27, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs752399257; hg19: chr10-103825280;