rs2296434

Positions:

Variant summary

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

The NM_000195.5(HPS1):c.1472C>G(p.Pro491Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 1,613,882 control chromosomes in the GnomAD database, including 7,326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 830 hom., cov: 32)

Exomes 𝑓: 0.090 ( 6496 hom. )

Consequence

HPS1
NM_000195.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.75

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017885268).

BP6

Variant 10-98423813-G-C is Benign according to our data. Variant chr10-98423813-G-C is described in ClinVar as [Benign]. Clinvar id is 21094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98423813-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 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.1472C>G	p.Pro491Arg	missense_variant	15/20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HPS1	ENST00000361490.9 linkuse as main transcript	c.1472C>G	p.Pro491Arg	missense_variant	15/20	1	NM_000195.5	ENSP00000355310.4	Q92902-1
ENSG00000289758	ENST00000699159.1 linkuse as main transcript	n.*831C>G		non_coding_transcript_exon_variant	14/24			ENSP00000514167.1	A0A8V8TP71
ENSG00000289758	ENST00000699159.1 linkuse as main transcript	n.*831C>G		3_prime_UTR_variant	14/24			ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15373

AN:

152114

Hom.:

827

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.128

Gnomad EAS

AF:

0.170

Gnomad SAS

AF:

0.0445

Gnomad FIN

AF:

0.134

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0851

Gnomad OTH

AF:

0.113

GnomAD3 exomes

AF:

0.107

AC:

26818

AN:

251010

Hom.:

1717

AF XY:

0.101

AC XY:

13658

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.107

Gnomad AMR exome

AF:

0.164

Gnomad ASJ exome

AF:

0.121

Gnomad EAS exome

AF:

0.186

Gnomad SAS exome

AF:

0.0402

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.0888

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.0903

AC:

132043

AN:

1461650

Hom.:

6496

Cov.:

AF XY:

0.0887

AC XY:

64518

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.110

Gnomad4 AMR exome

AF:

0.162

Gnomad4 ASJ exome

AF:

0.120

Gnomad4 EAS exome

AF:

0.161

Gnomad4 SAS exome

AF:

0.0424

Gnomad4 FIN exome

AF:

0.129

Gnomad4 NFE exome

AF:

0.0848

Gnomad4 OTH exome

AF:

0.0991

GnomAD4 genome

AF:

0.101

AC:

15395

AN:

152232

Hom.:

830

Cov.:

AF XY:

0.105

AC XY:

7811

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.105

Gnomad4 AMR

AF:

0.126

Gnomad4 ASJ

AF:

0.128

Gnomad4 EAS

AF:

0.171

Gnomad4 SAS

AF:

0.0446

Gnomad4 FIN

AF:

0.134

Gnomad4 NFE

AF:

0.0851

Gnomad4 OTH

AF:

0.111

Alfa

AF:

0.0832

Hom.:

463

Bravo

AF:

0.104

TwinsUK

AF:

0.0774

AC:

287

ALSPAC

AF:

0.0877

AC:

338

ESP6500AA

AF:

0.110

AC:

484

ESP6500EA

AF:

0.0845

AC:

727

ExAC

AF:

0.104

AC:

12650

EpiCase

AF:

0.0884

EpiControl

AF:

0.0872

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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	Pro491Arg in exon 15 of HPS1: This variant is not expected to have clinical sign ificance because it has been identified in 11.0% (484/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2296434). -

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

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

.;.;D;D

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;M;M;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.1

N;N;.;D

REVEL

Benign

0.16

Sift

Benign

0.070

T;T;.;D

Sift4G

Benign

0.095

T;T;T;T

Vest4

0.21

MPC

0.65

ClinPred

0.026

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.057

gMVP

0.35

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