3-149145364-A-G

Position:

chr3-149145364-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000296051.7(HPS3):c.981A>G(p.Thr327=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,610,020 control chromosomes in the GnomAD database, including 43,355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T327T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.27 ( 6353 hom., cov: 32)

Exomes 𝑓: 0.22 ( 37002 hom. )

Consequence

HPS3
ENST00000296051.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.177

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 3-149145364-A-G is Benign according to our data. Variant chr3-149145364-A-G is described in ClinVar as [Benign]. Clinvar id is 178777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.177 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS3	NM_032383.5 linkuse as main transcript	c.981A>G	p.Thr327=	synonymous_variant	5/17	ENST00000296051.7	NP_115759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS3	ENST00000296051.7 linkuse as main transcript	c.981A>G	p.Thr327=	synonymous_variant	5/17	1	NM_032383.5	ENSP00000296051	P1	Q969F9-1
HPS3	ENST00000460120.5 linkuse as main transcript	c.486A>G	p.Thr162=	synonymous_variant	4/16	2		ENSP00000418230
HPS3	ENST00000462030.5 linkuse as main transcript	n.1580A>G		non_coding_transcript_exon_variant	5/7	2
HPS3	ENST00000486530.1 linkuse as main transcript	n.1014A>G		non_coding_transcript_exon_variant	5/7	5

Frequencies

GnomAD3 genomes

AF:

0.274

AC:

41606

AN:

151900

Hom.:

6331

Cov.:

show subpopulations

Gnomad AFR

AF:

0.424

Gnomad AMI

AF:

0.0934

Gnomad AMR

AF:

0.252

Gnomad ASJ

AF:

0.203

Gnomad EAS

AF:

0.158

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.274

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.206

Gnomad OTH

AF:

0.245

GnomAD3 exomes

AF:

0.239

AC:

60093

AN:

251098

Hom.:

7746

AF XY:

0.233

AC XY:

31681

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.435

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.199

Gnomad EAS exome

AF:

0.151

Gnomad SAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.276

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.220

GnomAD4 exome

AF:

0.220

AC:

321145

AN:

1458002

Hom.:

37002

Cov.:

AF XY:

0.220

AC XY:

159676

AN XY:

725512

show subpopulations

Gnomad4 AFR exome

AF:

0.433

Gnomad4 AMR exome

AF:

0.290

Gnomad4 ASJ exome

AF:

0.201

Gnomad4 EAS exome

AF:

0.147

Gnomad4 SAS exome

AF:

0.240

Gnomad4 FIN exome

AF:

0.271

Gnomad4 NFE exome

AF:

0.210

Gnomad4 OTH exome

AF:

0.230

GnomAD4 genome

AF:

0.274

AC:

41677

AN:

152018

Hom.:

6353

Cov.:

AF XY:

0.276

AC XY:

20510

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.425

Gnomad4 AMR

AF:

0.252

Gnomad4 ASJ

AF:

0.203

Gnomad4 EAS

AF:

0.157

Gnomad4 SAS

AF:

0.237

Gnomad4 FIN

AF:

0.274

Gnomad4 NFE

AF:

0.206

Gnomad4 OTH

AF:

0.247

Alfa

AF:

0.222

Hom.:

5378

Bravo

AF:

0.280

Asia WGS

AF:

0.243

AC:

846

AN:

3478

EpiCase

AF:

0.209

EpiControl

AF:

0.202

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	Thr327Thr in exon 5 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 42.8% (1887/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs11718908). -

Hermansky-Pudlak syndrome 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 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. -

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

-0.84

CADD

Benign

2.2

DANN

Benign

0.54

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