rs281865076

Variant summary

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

The NM_000195.5(HPS1):c.391C>T(p.Arg131Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HPS1
NM_000195.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.18

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 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 10-98435279-G-A is Pathogenic according to our data. Variant chr10-98435279-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 21104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98435279-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5 linkuse as main transcript	c.391C>T	p.Arg131Ter	stop_gained	5/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9 linkuse as main transcript	c.391C>T	p.Arg131Ter	stop_gained	5/20	1	NM_000195.5	P1	Q92902-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251160

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 20, 2021	HPS1 c.391C>T has been reported in multiple individuals with Hermansky-Pudlak syndrome 1. This variant (rs281865076) is rare (<0.1%) in a large population dataset (gnomAD: 1/251160 total alleles; 0.0004%; no homozygotes) and has been reported in ClinVar. This nonsense variant results in a premature stop codon in exon 5 likely leading to nonsense-mediated decay and lack of protein production. We consider HPS1 c.391C>T to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 28, 2023	- -

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.Arg131Ter variant in HPS1 has been reported in 2 individuals with Hermansky-Pudlak syndrome (PMID: 14510955, 21458243), and has been identified in 0.003% (1/34584) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs281865076). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant was found to be de novo in 1 individual with confirmed paternity and maternity (PMID: 14510955). Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg131Ter variant is pathogenic (VariationID: 5278; PMID: 14510955). This variant has also been reported in ClinVar (Variation ID#: 21104) and has been interpreted as pathogenic by GeneReviews and Invitae. In vitro functional studies provide some evidence that the p.Arg131Ter variant may impact protein function (PMID: 14510955). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 131, which is 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, PM2_supporting, PVS1, PS3_moderate, PS2 (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 11, 2021	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 04, 2023

This sequence change creates a premature translational stop signal (p.Arg131*) 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 (rs281865076, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with HPS1-related conditions (PMID: 14510955, 21458243). ClinVar contains an entry for this variant (Variation ID: 21104). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.62

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

A;A;A

Vest4

0.88

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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