10-98420094-T-C

Variant names:

• chr10-98420094-T-C
• rs2296436
• NM_000195.5:c.1808A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict 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. 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/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.34
• Publications: 27 publications found

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

ENSG00000289758 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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/Likely_benign. ClinVar VariationId is 21099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000195.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	NM_000195.5	MANE Select	c.1808A>G	p.Gln603Arg	missense	Exon 18 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.1808A>G	p.Gln603Arg	missense	Exon 18 of 20	NP_001309405.1
	HPS1	NM_001322477.2		c.1808A>G	p.Gln603Arg	missense	Exon 18 of 20	NP_001309406.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.1808A>G	p.Gln603Arg	missense	Exon 18 of 20	ENSP00000355310.4
	HPS1	ENST00000467246.5	TSL:1	n.*1167A>G		non_coding_transcript_exon	Exon 17 of 19	ENSP00000514163.1
	ENSG00000289758	ENST00000699159.1		n.*1167A>G		non_coding_transcript_exon	Exon 17 of 24	ENSP00000514167.1

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

GnomAD2 exomes AF: 0.0999 AC: 25061 AN: 250894 AF XY: 0.0948

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 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

African (AFR) AF: 0.140 AC: 4700 AN: 33466

American (AMR) AF: 0.124 AC: 5565 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3066 AN: 26128

East Asian (EAS) AF: 0.121 AC: 4793 AN: 39696

South Asian (SAS) AF: 0.0410 AC: 3539 AN: 86246

European-Finnish (FIN) AF: 0.129 AC: 6883 AN: 53392

Middle Eastern (MID) AF: 0.122 AC: 704 AN: 5768

European-Non Finnish (NFE) AF: 0.0845 AC: 93962 AN: 1111654

Other (OTH) AF: 0.0983 AC: 5933 AN: 60374

GnomAD4 genome AF: 0.106 AC: 16081 AN: 152242 Hom.: 895 Cov.: 33 AF XY: 0.109 AC XY: 8100 AN XY: 74454

African (AFR) AF: 0.132 AC: 5505 AN: 41548

American (AMR) AF: 0.110 AC: 1687 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3468

East Asian (EAS) AF: 0.140 AC: 723 AN: 5180

South Asian (SAS) AF: 0.0424 AC: 204 AN: 4814

European-Finnish (FIN) AF: 0.134 AC: 1417 AN: 10610

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0849 AC: 5773 AN: 67998

Other (OTH) AF: 0.114 AC: 240 AN: 2112

Alfa AF: 0.0937 Hom.: 2394

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/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

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

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).

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

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

Jul 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hermansky-Pudlak syndrome 1 Benign:2

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

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 v4.9

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
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N
PhyloP100		1.3
PrimateAI	Benign	0.23	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.027
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.016
MPC		0.15
ClinPred		0.0032	T
GERP RS		3.4
Varity_R		0.028
gMVP		0.39
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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