rs6440589

chr3-149155200-G-Achr3-149155200-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032383.5(HPS3):c.1494G>A(p.Gln498=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,539,766 control chromosomes in the GnomAD database, including 161,541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19977 hom., cov: 32)
  • Exomes 𝑓: 0.45 (141564 hom.)
• Consequence: HPS3 NM_032383.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.264

Genes affected

HPS3 (HGNC:15597): (HPS3 biogenesis of lysosomal organelles complex 2 subunit 1) This gene encodes a protein containing a potential clathrin-binding motif, consensus dileucine signals, and tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. The encoded protein may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 3. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-149155200-G-A is Benign according to our data. Variant chr3-149155200-G-A is described in ClinVar as [Benign]. Clinvar id is 163668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.264 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS3	NM_032383.5	c.1494G>A	p.Gln498=	synonymous_variant	8/17	ENST00000296051.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS3	ENST00000296051.7	c.1494G>A	p.Gln498=	synonymous_variant	8/17	1	NM_032383.5	P1
HPS3	ENST00000460120.5	c.999G>A	p.Gln333=	synonymous_variant	7/16	2

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76190 AN: 151860 Hom.: 19945 Cov.: 32

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.462

GnomAD3 exomes AF: 0.445 AC: 111431 AN: 250662 Hom.: 25980 AF XY: 0.448 AC XY: 60649 AN XY: 135464

Gnomad AFR exome AF: 0.672

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.365

Gnomad SAS exome AF: 0.508

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.447 AC: 620305 AN: 1387788 Hom.: 141564 Cov.: 24 AF XY: 0.449 AC XY: 312084 AN XY: 694724

Gnomad4 AFR exome AF: 0.665

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.399

Gnomad4 EAS exome AF: 0.359

Gnomad4 SAS exome AF: 0.504

Gnomad4 FIN exome AF: 0.467

Gnomad4 NFE exome AF: 0.445

Gnomad4 OTH exome AF: 0.455

GnomAD4 genome AF: 0.502 AC: 76272 AN: 151978 Hom.: 19977 Cov.: 32 AF XY: 0.499 AC XY: 37091 AN XY: 74302

Gnomad4 AFR AF: 0.660

Gnomad4 AMR AF: 0.378

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.368

Gnomad4 SAS AF: 0.512

Gnomad4 FIN AF: 0.473

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.463

Alfa AF: 0.453 Hom.: 19561

Bravo AF: 0.498

Asia WGS AF: 0.451 AC: 1570 AN: 3478

EpiCase AF: 0.436

EpiControl AF: 0.438

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	Gln498Gln in exon 8 of HPS3: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 43.8% (3771/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs6440589). -

Hermansky-Pudlak syndrome 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.1
Dann	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs6440589; hg19: chr3-148872987; COSMIC: COSV56055838; COSMIC: COSV56055838;