rs11592273

chr10-98429811-C-Achr10-98429811-C-Gchr10-98429811-C-T

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.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 NM_000195.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.55

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=0.0026259422).
• 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	UniProt
HPS1	NM_000195.5	c.847G>T	p.Gly283Trp	missense_variant	9/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.847G>T	p.Gly283Trp	missense_variant	9/20	1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.0502 AC: 7645 AN: 152196 Hom.: 238 Cov.: 33

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

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.: 34 AF XY: 0.0663 AC XY: 48199 AN XY: 727046

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.: 33 AF XY: 0.0488 AC XY: 3635 AN XY: 74466

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2018	- -

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	T
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	N
MetaRNN	Benign	0.0026	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
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	T
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

Other links and lift over

dbSNP: rs11592273; hg19: chr10-100189568; COSMIC: COSV57266763; COSMIC: COSV57266763;