rs34197730

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_032383.5(HPS3):c.1479G>A(p.Thr493Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,590,148 control chromosomes in the GnomAD database, including 1,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 79 hom., cov: 33)

Exomes 𝑓: 0.035 ( 1013 hom. )

Consequence

HPS3
NM_032383.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.19

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 links:

HPS3 (HGNC:):

HPS3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 3-149155185-G-A is Benign according to our data. Variant chr3-149155185-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.19 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0312 (4752/152212) while in subpopulation SAS AF= 0.0452 (218/4822). AF 95% confidence interval is 0.0403. There are 79 homozygotes in gnomad4. There are 2331 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 79 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS3	NM_032383.5 linkuse as main transcript	c.1479G>A	p.Thr493Thr	synonymous_variant	8/17	ENST00000296051.7	NP_115759.2	Q969F9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS3	ENST00000296051.7 linkuse as main transcript	c.1479G>A	p.Thr493Thr	synonymous_variant	8/17	1	NM_032383.5	ENSP00000296051.2		Q969F9-1
HPS3	ENST00000460120.5 linkuse as main transcript	c.984G>A	p.Thr328Thr	synonymous_variant	7/16	2		ENSP00000418230.1		G5E9V4

Frequencies

GnomAD3 genomes

AF:

0.0313

AC:

4756

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0296

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0203

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0452

Gnomad FIN

AF:

0.0407

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0358

Gnomad OTH

AF:

0.0316

GnomAD3 exomes

AF:

0.0322

AC:

8065

AN:

250838

Hom.:

171

AF XY:

0.0344

AC XY:

4657

AN XY:

135522

show subpopulations

Gnomad AFR exome

AF:

0.0312

Gnomad AMR exome

AF:

0.0170

Gnomad ASJ exome

AF:

0.0165

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0493

Gnomad FIN exome

AF:

0.0459

Gnomad NFE exome

AF:

0.0359

Gnomad OTH exome

AF:

0.0393

GnomAD4 exome

AF:

0.0348

AC:

49981

AN:

1437936

Hom.:

1013

Cov.:

AF XY:

0.0356

AC XY:

25488

AN XY:

716904

show subpopulations

Gnomad4 AFR exome

AF:

0.0295

Gnomad4 AMR exome

AF:

0.0176

Gnomad4 ASJ exome

AF:

0.0152

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.0509

Gnomad4 FIN exome

AF:

0.0455

Gnomad4 NFE exome

AF:

0.0356

Gnomad4 OTH exome

AF:

0.0316

GnomAD4 genome

AF:

0.0312

AC:

4752

AN:

152212

Hom.:

Cov.:

AF XY:

0.0313

AC XY:

2331

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0295

Gnomad4 AMR

AF:

0.0203

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0452

Gnomad4 FIN

AF:

0.0407

Gnomad4 NFE

AF:

0.0358

Gnomad4 OTH

AF:

0.0298

Alfa

AF:

0.0290

Hom.:

Bravo

AF:

0.0296

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0339

EpiControl

AF:

0.0352

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr493Thr 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 3.4% (294/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs34197730). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hermansky-Pudlak syndrome 3

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

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.7

DANN

Benign

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over