3-149163886-C-T

Variant names:

Variant summary

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

The NM_032383.5(HPS3):c.2526C>T(p.His842His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,567,320 control chromosomes in the GnomAD database, including 29,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2511 hom., cov: 32)

Exomes 𝑓: 0.19 ( 27392 hom. )

Consequence

HPS3
NM_032383.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.484

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:

CP (HGNC:2295): (ceruloplasmin) The protein encoded by this gene is a metalloprotein that binds most of the copper in plasma and is involved in the peroxidation of Fe(II)transferrin to Fe(III) transferrin. Mutations in this gene cause aceruloplasminemia, which results in iron accumulation and tissue damage, and is associated with diabetes and neurologic abnormalities. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Feb 2012]

CP 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=-0.71).

BP6

Variant 3-149163886-C-T is Benign according to our data. Variant chr3-149163886-C-T is described in ClinVar as [Benign]. Clinvar id is 163669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.484 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS3	NM_032383.5 link	c.2526C>T	p.His842His	synonymous_variant	Exon 14 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.2526C>T	p.His842His	synonymous_variant	Exon 14 of 17	1	NM_032383.5	ENSP00000296051.2		Q969F9-1

Frequencies

GnomAD3 genomes

AF:

0.160

AC:

24256

AN:

152014

Hom.:

2513

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0437

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.273

Gnomad SAS

AF:

0.215

Gnomad FIN

AF:

0.274

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.206

Gnomad OTH

AF:

0.135

GnomAD3 exomes

AF:

0.186

AC:

46378

AN:

249622

Hom.:

4870

AF XY:

0.190

AC XY:

25609

AN XY:

134952

show subpopulations

Gnomad AFR exome

AF:

0.0395

Gnomad AMR exome

AF:

0.125

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.278

Gnomad SAS exome

AF:

0.204

Gnomad FIN exome

AF:

0.255

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.168

GnomAD4 exome

AF:

0.189

AC:

267329

AN:

1415188

Hom.:

27392

Cov.:

AF XY:

0.191

AC XY:

134558

AN XY:

706272

show subpopulations

Gnomad4 AFR exome

AF:

0.0347

Gnomad4 AMR exome

AF:

0.127

Gnomad4 ASJ exome

AF:

0.106

Gnomad4 EAS exome

AF:

0.259

Gnomad4 SAS exome

AF:

0.202

Gnomad4 FIN exome

AF:

0.251

Gnomad4 NFE exome

AF:

0.193

Gnomad4 OTH exome

AF:

0.179

GnomAD4 genome

AF:

0.159

AC:

24258

AN:

152132

Hom.:

2511

Cov.:

AF XY:

0.163

AC XY:

12104

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0436

Gnomad4 AMR

AF:

0.141

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.274

Gnomad4 SAS

AF:

0.216

Gnomad4 FIN

AF:

0.274

Gnomad4 NFE

AF:

0.206

Gnomad4 OTH

AF:

0.135

Alfa

AF:

0.176

Hom.:

3843

Bravo

AF:

0.143

Asia WGS

AF:

0.215

AC:

750

AN:

3478

EpiCase

AF:

0.185

EpiControl

AF:

0.183

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

His842His in exon 14 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 18.9% (1627/8596) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs3732557). -

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 13, 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

-0.71

CADD

Benign

6.2

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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