rs281865163

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000195.5(HPS1):c.1487_1488insCCAGCAGGGGAGGCCC(p.His497GlnfsTer90) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,014 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 2 hom. )

Consequence

HPS1
NM_000195.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 3.27

Variant links:

Genes affected

HPS1 (HGNC:5163): (HPS1 biogenesis of lysosomal organelles complex 3 subunit 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is a component of three different protein complexes termed biogenesis of lysosome-related organelles complex (BLOC)-3, BLOC4, and BLOC5. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 1. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on chromosome 22. [provided by RefSeq, Aug 2015]

HPS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 10-98423797-T-TGGGCCTCCCCTGCTGG is Pathogenic according to our data. Variant chr10-98423797-T-TGGGCCTCCCCTGCTGG is described in ClinVar as [Pathogenic]. Clinvar id is 5277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5 linkuse as main transcript	c.1487_1488insCCAGCAGGGGAGGCCC	p.His497GlnfsTer90	frameshift_variant	15/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9 linkuse as main transcript	c.1487_1488insCCAGCAGGGGAGGCCC	p.His497GlnfsTer90	frameshift_variant	15/20	1	NM_000195.5	P1	Q92902-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

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:

0.00

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251090

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000604

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:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000361

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 1

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 30, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 16, 2022	- -
Pathogenic, no assertion criteria provided	research	Genomics And Bioinformatics Analysis Resource, Columbia University	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Oct 19, 2018	- -

Hermansky-Pudlak syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2023	The p.His497GlnfsX90 variant in HPS1 has been reported in the homozygous or compound heterozygous state in >20 individuals with Hermansky-Pudlak syndrome and has been described as founder variant in Puerto Rican population (Oh 1996 PMID: 8896559, Carmona-Rivera 2010 PMID: 20662851). It has been identified in 0.02% (7/35412) of Latino/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 5277). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 497 and leads to a premature termination codon 90 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HPS1 gene is an established disease mechanism in Hermansky-Pudlak syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hermansky-Pudlak syndrome. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 29, 2021	The p.His497fs variant in HPS1 has been reported in more than 10 individuals with Hermansky-Pudlak syndrome (PMID: 8896559, 20662851, 12442288, 9562579, 9497254) and has been identified in 0.03% (7/35412) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs281865163). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 5277) and has been interpreted as Pathogenic by GeneReviews, Genetic Services Laboratory (University of Chicago), Clinical Molecular Genetics Laboratory (Johns Hopkins All Children's Hospital), Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), Ambry Genetics, Invitae, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), GeneDx, OMIM, and Natera, Inc. In vitro functional studies provide some evidence that the p.His497fs variant may slightly impact protein function (PMID: 9345105). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 497 and leads to a premature termination codon 90 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HPS1 gene is an established disease mechanism in autosomal recessive Hermansky-Pudlak syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hermansky-Pudlak syndrome. ACMG/AMP Criteria applied: PM3, PS3_moderate, PVS1 (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change creates a premature translational stop signal (p.His497Glnfs*90) in the HPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS1 are known to be pathogenic (PMID: 12442288, 16185271). This variant is present in population databases (rs281865163, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Hermansky-Pudlak syndrome (PMID: 8896559, 9562579, 20662851). It is commonly reported in individuals of Puerto Rican ancestry (PMID: 8896559, 9562579, 20662851). ClinVar contains an entry for this variant (Variation ID: 5277). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2020	Frameshift variant that results in nonsense mediated mRNA decay (Hazelwood et al., 1997) in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29445374, 8896559, 9345105, 30055995, 20662851, 9562579, 31898847) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2018

- -

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

Other links and lift over