rs2296434

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P491S) has been classified as Uncertain significance.

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/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.75

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
Hermansky-Pudlak syndrome with pulmonary fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HPS1 links:

ENSG00000289758 (HGNC:):

ENSG00000289758 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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/Likely_benign. ClinVar VariationId is 21094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5 link	c.1472C>G	p.Pro491Arg	missense_variant	Exon 15 of 20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HPS1	ENST00000361490.9 link	c.1472C>G	p.Pro491Arg	missense_variant	Exon 15 of 20	1	NM_000195.5	ENSP00000355310.4
ENSG00000289758	ENST00000699159.1 link	n.*831C>G		non_coding_transcript_exon_variant	Exon 14 of 24			ENSP00000514167.1
ENSG00000289758	ENST00000699159.1 link	n.*831C>G		3_prime_UTR_variant	Exon 14 of 24			ENSP00000514167.1

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

GnomAD2 exomes

AF:

0.107

AC:

26818

AN:

251010

AF XY:

0.101

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 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

African (AFR)

AF:

0.110

AC:

3697

AN:

33474

American (AMR)

AF:

0.162

AC:

7253

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

3126

AN:

26136

East Asian (EAS)

AF:

0.161

AC:

6405

AN:

39700

South Asian (SAS)

AF:

0.0424

AC:

3658

AN:

86254

European-Finnish (FIN)

AF:

0.129

AC:

6888

AN:

53272

Middle Eastern (MID)

AF:

0.125

AC:

714

AN:

5718

European-Non Finnish (NFE)

AF:

0.0848

AC:

94315

AN:

1111992

Other (OTH)

AF:

0.0991

AC:

5987

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

7793

15587

23380

31174

38967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3604

7208

10812

14416

18020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.101

AC:

15395

AN:

152232

Hom.:

830

Cov.:

AF XY:

0.105

AC XY:

7811

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.105

AC:

4379

AN:

41546

American (AMR)

AF:

0.126

AC:

1934

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

444

AN:

3472

East Asian (EAS)

AF:

0.171

AC:

879

AN:

5154

South Asian (SAS)

AF:

0.0446

AC:

215

AN:

4824

European-Finnish (FIN)

AF:

0.134

AC:

1424

AN:

10612

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0851

AC:

5785

AN:

68000

Other (OTH)

AF:

0.111

AC:

235

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

719

1438

2157

2876

3595

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Feb 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome 1

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

2.7

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over