10-98420094-T-C

Position:

chr10-98420094-T-C

Variant summary

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

The NM_000195.5(HPS1):c.1808A>G(p.Gln603Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.09 in 1,613,678 control chromosomes in the GnomAD database, including 7,029 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 (★★).

Frequency

Genomes: 𝑓 0.11 ( 895 hom., cov: 33)

Exomes 𝑓: 0.088 ( 6134 hom. )

Consequence

HPS1
NM_000195.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.34

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 (MetaRNN=0.0013628304).

BP6

Variant 10-98420094-T-C is Benign according to our data. Variant chr10-98420094-T-C is described in ClinVar as [Benign]. Clinvar id is 21099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98420094-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 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.1808A>G	p.Gln603Arg	missense_variant	18/20	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.1808A>G	p.Gln603Arg	missense_variant	18/20	1	NM_000195.5	ENSP00000355310.4	Q92902-1
ENSG00000289758	ENST00000699159.1 linkuse as main transcript	n.*1167A>G		non_coding_transcript_exon_variant	17/24			ENSP00000514167.1	A0A8V8TP71
ENSG00000289758	ENST00000699159.1 linkuse as main transcript	n.*1167A>G		3_prime_UTR_variant	17/24			ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16067

AN:

152124

Hom.:

894

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.139

Gnomad SAS

AF:

0.0423

Gnomad FIN

AF:

0.134

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0850

Gnomad OTH

AF:

0.115

GnomAD3 exomes

AF:

0.0999

AC:

25061

AN:

250894

Hom.:

1464

AF XY:

0.0948

AC XY:

12862

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.125

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.145

Gnomad SAS exome

AF:

0.0390

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.0883

Gnomad OTH exome

AF:

0.109

GnomAD4 exome

AF:

0.0884

AC:

129145

AN:

1461436

Hom.:

6134

Cov.:

AF XY:

0.0869

AC XY:

63164

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.140

Gnomad4 AMR exome

AF:

0.124

Gnomad4 ASJ exome

AF:

0.117

Gnomad4 EAS exome

AF:

0.121

Gnomad4 SAS exome

AF:

0.0410

Gnomad4 FIN exome

AF:

0.129

Gnomad4 NFE exome

AF:

0.0845

Gnomad4 OTH exome

AF:

0.0983

GnomAD4 genome

AF:

0.106

AC:

16081

AN:

152242

Hom.:

895

Cov.:

AF XY:

0.109

AC XY:

8100

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.132

Gnomad4 AMR

AF:

0.110

Gnomad4 ASJ

AF:

0.125

Gnomad4 EAS

AF:

0.140

Gnomad4 SAS

AF:

0.0424

Gnomad4 FIN

AF:

0.134

Gnomad4 NFE

AF:

0.0849

Gnomad4 OTH

AF:

0.114

Alfa

AF:

0.0916

Hom.:

1666

Bravo

AF:

0.107

TwinsUK

AF:

0.0782

AC:

290

ALSPAC

AF:

0.0882

AC:

340

ESP6500AA

AF:

0.139

AC:

614

ESP6500EA

AF:

0.0847

AC:

728

ExAC

AF:

0.0990

AC:

12023

Asia WGS

AF:

0.0930

AC:

324

AN:

3478

EpiCase

AF:

0.0876

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	GeneDx	Jul 25, 2019	- -
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	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Gln603Arg in exon 18 of HPS1: This variant is not expected to have clinical sign ificance because it has been identified in 13.9% (614/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2296436). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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 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. -

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

0.055

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.71

CADD

Benign

9.1

DANN

Benign

0.78

DEOGEN2

Benign

0.058

T;T;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.71

.;.;T

MetaRNN

Benign

0.0014

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.0

N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

1.0

N;N;.

REVEL

Benign

0.027

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;T

Vest4

0.016

MPC

0.15

ClinPred

0.0032

GERP RS

3.4

Varity_R

0.028

gMVP

0.39

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