rs34388030

Positions:

chr3-149141127-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032383.5(HPS3):c.823G>A(p.Glu275Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000999 in 1,613,236 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 9 hom. )

Consequence

HPS3
NM_032383.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.18

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008656204).

BP6

Variant 3-149141127-G-A is Benign according to our data. Variant chr3-149141127-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00544 (824/151494) while in subpopulation AFR AF= 0.0196 (807/41270). AF 95% confidence interval is 0.0184. There are 6 homozygotes in gnomad4. There are 384 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS3	NM_032383.5 linkuse as main transcript	c.823G>A	p.Glu275Lys	missense_variant	3/17	ENST00000296051.7	NP_115759.2	Q969F9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HPS3	ENST00000296051.7 linkuse as main transcript	c.823G>A	p.Glu275Lys	missense_variant	3/17	1	NM_032383.5	ENSP00000296051.2	Q969F9-1
HPS3	ENST00000460120.5 linkuse as main transcript	c.328G>A	p.Glu110Lys	missense_variant	2/16	2		ENSP00000418230.1	G5E9V4
HPS3	ENST00000462030.5 linkuse as main transcript	n.1422G>A		non_coding_transcript_exon_variant	3/7	2
HPS3	ENST00000486530.1 linkuse as main transcript	n.856G>A		non_coding_transcript_exon_variant	3/7	5

Frequencies

GnomAD3 genomes

AF:

0.00542

AC:

821

AN:

151432

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000853

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00137

AC:

345

AN:

251414

Hom.:

AF XY:

0.000949

AC XY:

129

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0194

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000538

AC:

787

AN:

1461742

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

333

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0200

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.00544

AC:

824

AN:

151494

Hom.:

Cov.:

AF XY:

0.00520

AC XY:

384

AN XY:

73898

show subpopulations

Gnomad4 AFR

AF:

0.0196

Gnomad4 AMR

AF:

0.000852

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000789

Hom.:

Bravo

AF:

0.00573

ESP6500AA

AF:

0.0191

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00180

AC:

218

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Glu275Lys in exon 3 of HPS3: This variant is not expected to have clinical signi ficance because it has been identified in 1.9% (84/4406) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs34388030). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 31, 2019	- -

Hermansky-Pudlak syndrome 3

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2017	- -
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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Hermansky-Pudlak syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;T

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0087

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.24

Sift

Uncertain

0.012

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.77

MVP

0.88

MPC

0.60

ClinPred

0.036

GERP RS

5.7

Varity_R

0.35

gMVP

0.71

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

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