rs11539873

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001311345.2(HPS1):c.-620C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0603 in 1,613,862 control chromosomes in the GnomAD database, including 3,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 250 hom., cov: 32)

Exomes 𝑓: 0.061 ( 2939 hom. )

Consequence

HPS1
NM_001311345.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.47

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:

ENSG00000289758 (HGNC:):

ENSG00000289758 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 10-98435373-G-A is Benign according to our data. Variant chr10-98435373-G-A is described in ClinVar as [Benign]. Clinvar id is 163666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS1	NM_000195.5 linkuse as main transcript	c.297C>T	p.Thr99Thr	synonymous_variant	5/20	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.297C>T	p.Thr99Thr	synonymous_variant	5/20	1	NM_000195.5	ENSP00000355310.4		Q92902-1
ENSG00000289758	ENST00000699159.1 linkuse as main transcript	n.297C>T		non_coding_transcript_exon_variant	5/24			ENSP00000514167.1		A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.0508

AC:

7725

AN:

152036

Hom.:

250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0125

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0541

Gnomad ASJ

AF:

0.121

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.0360

Gnomad FIN

AF:

0.0677

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0610

Gnomad OTH

AF:

0.0707

GnomAD3 exomes

AF:

0.0656

AC:

16495

AN:

251304

Hom.:

668

AF XY:

0.0640

AC XY:

8695

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.0107

Gnomad AMR exome

AF:

0.0662

Gnomad ASJ exome

AF:

0.118

Gnomad EAS exome

AF:

0.145

Gnomad SAS exome

AF:

0.0324

Gnomad FIN exome

AF:

0.0680

Gnomad NFE exome

AF:

0.0641

Gnomad OTH exome

AF:

0.0697

GnomAD4 exome

AF:

0.0613

AC:

89555

AN:

1461708

Hom.:

2939

Cov.:

AF XY:

0.0606

AC XY:

44093

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0101

Gnomad4 AMR exome

AF:

0.0649

Gnomad4 ASJ exome

AF:

0.116

Gnomad4 EAS exome

AF:

0.121

Gnomad4 SAS exome

AF:

0.0336

Gnomad4 FIN exome

AF:

0.0683

Gnomad4 NFE exome

AF:

0.0605

Gnomad4 OTH exome

AF:

0.0684

GnomAD4 genome

AF:

0.0507

AC:

7719

AN:

152154

Hom.:

250

Cov.:

AF XY:

0.0526

AC XY:

3914

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0124

Gnomad4 AMR

AF:

0.0541

Gnomad4 ASJ

AF:

0.121

Gnomad4 EAS

AF:

0.136

Gnomad4 SAS

AF:

0.0362

Gnomad4 FIN

AF:

0.0677

Gnomad4 NFE

AF:

0.0610

Gnomad4 OTH

AF:

0.0691

Alfa

AF:

0.0587

Hom.:

199

Bravo

AF:

0.0497

Asia WGS

AF:

0.0660

AC:

230

AN:

3478

EpiCase

AF:

0.0664

EpiControl

AF:

0.0672

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr99Thr in exon 5 of HPS1: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 6.0% (512/8600) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11539873). -

Hermansky-Pudlak syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hermansky-Pudlak syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.023

DANN

Benign

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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