rs6440589

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_032383.5(HPS3):c.1494G>A(p.Gln498Gln) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.264

Publications

20 publications found

Variant links:

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]

HPS3 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
Hermansky-Pudlak syndrome without pulmonary fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HPS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HPS3	NM_032383.5 link	c.1494G>A	p.Gln498Gln	synonymous_variant	Exon 8 of 17	ENST00000296051.7	NP_115759.2	Q969F9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS3	ENST00000296051.7 link	c.1494G>A	p.Gln498Gln	synonymous_variant	Exon 8 of 17	1	NM_032383.5	ENSP00000296051.2		Q969F9-1
HPS3	ENST00000460120.5 link	c.999G>A	p.Gln333Gln	synonymous_variant	Exon 7 of 16	2		ENSP00000418230.1		G5E9V4

Frequencies

GnomAD3 genomes

AF:

0.502

AC:

76190

AN:

151860

Hom.:

19945

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.445

AC:

111431

AN:

250662

AF XY:

0.448

show subpopulations

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 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.:

AF XY:

0.449

AC XY:

312084

AN XY:

694724

show subpopulations

African (AFR)

AF:

0.665

AC:

21159

AN:

31806

American (AMR)

AF:

0.303

AC:

13526

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

10254

AN:

25694

East Asian (EAS)

AF:

0.359

AC:

14128

AN:

39322

South Asian (SAS)

AF:

0.504

AC:

42597

AN:

84546

European-Finnish (FIN)

AF:

0.467

AC:

24899

AN:

53332

Middle Eastern (MID)

AF:

0.408

AC:

2301

AN:

5638

European-Non Finnish (NFE)

AF:

0.445

AC:

465054

AN:

1044892

Other (OTH)

AF:

0.455

AC:

26387

AN:

57950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

14486

28972

43457

57943

72429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.502

AC:

76272

AN:

151978

Hom.:

19977

Cov.:

AF XY:

0.499

AC XY:

37091

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.660

AC:

27338

AN:

41434

American (AMR)

AF:

0.378

AC:

5773

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.389

AC:

1349

AN:

3468

East Asian (EAS)

AF:

0.368

AC:

1902

AN:

5170

South Asian (SAS)

AF:

0.512

AC:

2471

AN:

4822

European-Finnish (FIN)

AF:

0.473

AC:

4995

AN:

10554

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.456

AC:

31012

AN:

67958

Other (OTH)

AF:

0.463

AC:

975

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1884

3768

5653

7537

9421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.471

Hom.:

29830

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

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). -

Feb 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hermansky-Pudlak syndrome 3

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.1

(source)

DANN

Benign

0.30

PhyloP100

-0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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rs6440589

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over