10-98420094-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q603W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (895 hom., cov: 33)
  • Exomes 𝑓: 0.088 (6134 hom.)
• Consequence: HPS1 NM_000195.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.34

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]

ACMG classification

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	UniProt
HPS1	NM_000195.5	c.1808A>G	p.Gln603Arg	missense_variant	18/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.1808A>G	p.Gln603Arg	missense_variant	18/20	1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16067 AN: 152124 Hom.: 894 Cov.: 33

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

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.: 31 AF XY: 0.0869 AC XY: 63164 AN XY: 727018

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.: 33 AF XY: 0.109 AC XY: 8100 AN XY: 74454

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	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). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hermansky-Pudlak syndrome 1 Benign:2

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	- -

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	T
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	N
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N;N;N
MutationTaster	Benign	0.020	P;P
PrimateAI	Benign	0.23	T
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	T
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

Other links and lift over

dbSNP: rs2296436; hg19: chr10-100179851; COSMIC: COSV57268041; COSMIC: COSV57268041;