Variant chr10-98427229-TG-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000361490.9(HPS1):c.972del(p.Met325TrpfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,535,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P324P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

HPS1
ENST00000361490.9 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 0.721

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-98427229-TG-T is Pathogenic according to our data. Variant chr10-98427229-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 5280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98427229-TG-T is described in Lovd as [Pathogenic]. Variant chr10-98427229-TG-T is described in Lovd as [Pathogenic]. Variant chr10-98427229-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS1	NM_000195.5 linkuse as main transcript	c.972del	p.Met325TrpfsTer6	frameshift_variant	11/20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9 linkuse as main transcript	c.972del	p.Met325TrpfsTer6	frameshift_variant	11/20	1	NM_000195.5	ENSP00000355310	P1	Q92902-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

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:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000455

AC:

AN:

1383570

Hom.:

Cov.:

AF XY:

0.0000425

AC XY:

AN XY:

682764

show subpopulations

Gnomad4 AFR exome

AF:

0.0000966

Gnomad4 AMR exome

AF:

0.0000566

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000848

Gnomad4 SAS exome

AF:

0.0000383

Gnomad4 FIN exome

AF:

0.000578

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000125

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 1

Pathogenic:4Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 07, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 09, 2019	DNA sequence analysis of the HPS1 gene demonstrated a one base pair deletion in exon 11, c.972del. This sequence change results in an amino acid frameshift and creates a premature stop codon 5 amino acids downstream of the sequence change, p.Met325Trpfs*6. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated HPS1 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a population frequency of 0.012% in African subpopulation (dbSNP rs281865082). This sequence change has previously been described in patients with Hermansky-Pudlak syndrome in both homozygous and compound heterozygous states (PMID: 20662851, PMID: 19334085, PMID: 8896559). Functional studies have shown results that suggest a lack of function of the protein (PMID: 21833017). These collective evidences indicate that this sequence change is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Met325Trpfs*6) 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). 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 individuals with Hermansky‚ÄìPudlak syndrome (PMID: 19334085, 27593200). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5280). For these reasons, this variant has been classified as Pathogenic. -

Hermansky-Pudlak syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 29, 2021	The p.Met325fs (c.972del) variant in HPS1 has been reported in at least 4 individuals with Hermansky-Pudlak syndrome (PMID: 27593200, 19334085, 9705234, 9497254), segregated with disease in 2 affected relatives from 2 families (PMID: 19334085, 9705234) and has been identified in 0.09% (15/17454) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs281865083). 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. It is of note that this variant occurs in a homopolymer repeat, which could indicate that it exists as an artifact from sequencing. However, disease-causing variants have been reported in homopolymer regions, so this is not enough to rule out a pathogenic role. Of the 4 affected individuals, 1 was compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Met325fs variant is pathogenic (VariationID: 21091; PMID: 9705234). This variant has also been reported in ClinVar (Variation ID#: 5280) and has been interpreted as pathogenic by Invitae, Nilou-Genome Lab, OMIM, Natera, Inc., and GeneReviews. In vitro functional studies provide some evidence that the p.Met325fs variant may impact protein function (PMID: 9705234). 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 325 and leads to a premature termination codon 6 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, PP1, PVS1 , PS3_moderate (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

HPS1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 28, 2024

The HPS1 c.972delC variant is predicted to result in a frameshift and premature protein termination (p.Met325Trpfs*6). This variant has reported in multiple individuals with Hermansky-Pudlak syndrome (Wei et al. 2016. PubMed ID: 27593200, Table S2, Liu et al. 2020. PubMed ID: 32725903). This variant is reported in 0.086% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in HPS1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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