rs11592273

Positions:

Variant summary

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

The ENST00000361490.9(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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G283A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.050 ( 238 hom., cov: 33)

Exomes 𝑓: 0.068 ( 3776 hom. )

Consequence

HPS1
ENST00000361490.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.55

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 Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
HPS1	NM_000195.5 linkuse as main transcript	c.847G>T	p.Gly283Trp	missense_variant	9/20	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.847G>T	p.Gly283Trp	missense_variant	9/20	1	NM_000195.5	ENSP00000355310	P1	Q92902-1

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

GnomAD3 exomes

AF:

0.0487

AC:

12218

AN:

251054

Hom.:

405

AF XY:

0.0489

AC XY:

6641

AN XY:

135782

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 SAS exome

AF:

0.0136

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

Gnomad4 AFR exome

AF:

0.0190

Gnomad4 AMR exome

AF:

0.0274

Gnomad4 ASJ exome

AF:

0.0213

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0141

Gnomad4 FIN exome

AF:

0.0684

Gnomad4 NFE exome

AF:

0.0793

Gnomad4 OTH exome

AF:

0.0584

GnomAD4 genome

AF:

0.0502

AC:

7645

AN:

152314

Hom.:

238

Cov.:

AF XY:

0.0488

AC XY:

3635

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0220

Gnomad4 AMR

AF:

0.0361

Gnomad4 ASJ

AF:

0.0234

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.0168

Gnomad4 FIN

AF:

0.0641

Gnomad4 NFE

AF:

0.0758

Gnomad4 OTH

AF:

0.0487

Alfa

AF:

0.0633

Hom.:

495

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2018	- -
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	-	- -

Hermansky-Pudlak syndrome 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

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	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

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

0.12

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.29

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

MutationTaster

Benign

1.0

N;N;N

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

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