rs11592273

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.847G>T(p.Gly283Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0662 in 1,613,760 control chromosomes in the GnomAD database, including 4,014 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G283R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.050 ( 238 hom., cov: 33)

Exomes 𝑓: 0.068 ( 3776 hom. )

Consequence

HPS1
NM_000195.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.55

Publications

19 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=0.0026259422).

BP6

Variant 10-98429811-C-A is Benign according to our data. Variant chr10-98429811-C-A is described in ClinVar as Benign. ClinVar VariationId is 21108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5 link	c.847G>T	p.Gly283Trp	missense_variant	Exon 9 of 20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9 link	c.847G>T	p.Gly283Trp	missense_variant	Exon 9 of 20	1	NM_000195.5	ENSP00000355310.4		Q92902-1
ENSG00000289758	ENST00000699159.1 link	n.*227-169G>T		intron_variant	Intron 8 of 23			ENSP00000514167.1		A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.0502

AC:

7645

AN:

152196

Hom.:

238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0221

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0361

Gnomad ASJ

AF:

0.0234

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.0167

Gnomad FIN

AF:

0.0641

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0758

Gnomad OTH

AF:

0.0492

GnomAD2 exomes

AF:

0.0487

AC:

12218

AN:

251054

AF XY:

0.0489

show subpopulations

Gnomad AFR exome

AF:

0.0227

Gnomad AMR exome

AF:

0.0266

Gnomad ASJ exome

AF:

0.0188

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0642

Gnomad NFE exome

AF:

0.0758

Gnomad OTH exome

AF:

0.0553

GnomAD4 exome

AF:

0.0679

AC:

99201

AN:

1461446

Hom.:

3776

Cov.:

AF XY:

0.0663

AC XY:

48199

AN XY:

727046

show subpopulations

African (AFR)

AF:

0.0190

AC:

635

AN:

33480

American (AMR)

AF:

0.0274

AC:

1225

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

558

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0141

AC:

1220

AN:

86256

European-Finnish (FIN)

AF:

0.0684

AC:

3627

AN:

53032

Middle Eastern (MID)

AF:

0.0442

AC:

255

AN:

5766

European-Non Finnish (NFE)

AF:

0.0793

AC:

88151

AN:

1111960

Other (OTH)

AF:

0.0584

AC:

3525

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

5323

10646

15969

21292

26615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3204

6408

9612

12816

16020

<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:

0.0502

AC:

7645

AN:

152314

Hom.:

238

Cov.:

AF XY:

0.0488

AC XY:

3635

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0220

AC:

915

AN:

41588

American (AMR)

AF:

0.0361

AC:

552

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

AN:

3468

East Asian (EAS)

AF:

0.000773

AC:

AN:

5172

South Asian (SAS)

AF:

0.0168

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0641

AC:

681

AN:

10618

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0758

AC:

5157

AN:

68012

Other (OTH)

AF:

0.0487

AC:

103

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

377

754

1130

1507

1884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0615

Hom.:

659

Bravo

AF:

0.0472

TwinsUK

AF:

0.0809

AC:

300

ALSPAC

AF:

0.0693

AC:

267

ESP6500AA

AF:

0.0302

AC:

133

ESP6500EA

AF:

0.0758

AC:

652

ExAC

AF:

0.0511

AC:

6205

EpiCase

AF:

0.0696

EpiControl

AF:

0.0740

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 19, 2018

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:3

Sep 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gly283Trp in exon 9 of HPS1: This variant is not expected to have clinical signi ficance because it has been identified in 7.6% (652/8600) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs11592273). -

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

0.12

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.29

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.076

T;T;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.35

.;.;T;T

MetaRNN

Benign

0.0026

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.4

L;L;L;L

PhyloP100

-1.5

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

N;N;.;N

REVEL

Benign

0.12

Sift

Benign

0.034

D;D;.;D

Sift4G

Benign

0.079

T;T;T;D

Polyphen

0.99

D;D;D;P

Vest4

0.14

MPC

0.49

ClinPred

0.038

GERP RS

-5.5

Varity_R

0.029

gMVP

0.22

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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