rs140443498

Positions:

chr3-149160228-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_032383.5(HPS3):c.2055G>A(p.Leu685Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,613,840 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 19 hom. )

Consequence

HPS3
NM_032383.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.29

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 3-149160228-G-A is Benign according to our data. Variant chr3-149160228-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-149160228-G-A is described in Lovd as [Benign]. Variant chr3-149160228-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.29 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00293 (446/152290) while in subpopulation NFE AF= 0.00475 (323/68022). AF 95% confidence interval is 0.00432. There are 2 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS3	NM_032383.5 linkuse as main transcript	c.2055G>A	p.Leu685Leu	synonymous_variant	11/17	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.2055G>A	p.Leu685Leu	synonymous_variant	11/17	1	NM_032383.5	ENSP00000296051.2	Q969F9-1
HPS3	ENST00000460120.5 linkuse as main transcript	c.1560G>A	p.Leu520Leu	synonymous_variant	10/16	2		ENSP00000418230.1	G5E9V4
HPS3	ENST00000460822.1 linkuse as main transcript	n.183G>A		non_coding_transcript_exon_variant	1/8	2		ENSP00000419824.1	H7C5G2

Frequencies

GnomAD3 genomes

AF:

0.00293

AC:

446

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00500

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00475

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00308

AC:

772

AN:

250788

Hom.:

AF XY:

0.00308

AC XY:

418

AN XY:

135546

show subpopulations

Gnomad AFR exome

AF:

0.000988

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.00471

Gnomad NFE exome

AF:

0.00483

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00473

AC:

6907

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00471

AC XY:

3423

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00138

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00133

Gnomad4 FIN exome

AF:

0.00502

Gnomad4 NFE exome

AF:

0.00559

Gnomad4 OTH exome

AF:

0.00335

GnomAD4 genome

AF:

0.00293

AC:

446

AN:

152290

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00500

Gnomad4 NFE

AF:

0.00475

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00361

Hom.:

Bravo

AF:

0.00289

EpiCase

AF:

0.00431

EpiControl

AF:

0.00528

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Leu685Leu in exon 11 of HPS3: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.5% (42/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs140443498). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hermansky-Pudlak syndrome 3

Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 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

-0.40

CADD

Benign

6.9

DANN

Benign

0.79

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