rs2296433

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000195.5(HPS1):c.1397+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,605,012 control chromosomes in the GnomAD database, including 51,037 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4112 hom., cov: 33)

Exomes 𝑓: 0.25 ( 46925 hom. )

Consequence

HPS1
NM_000195.5 splice_region, intron

Scores

Splicing: ADA: 0.0006200

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.466

Publications

12 publications found

Variant links:

Genes affected

HPS1 (HGNC:5163): (HPS1 biogenesis of lysosomal organelles complex 3 subunit 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is a component of three different protein complexes termed biogenesis of lysosome-related organelles complex (BLOC)-3, BLOC4, and BLOC5. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 1. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on chromosome 22. [provided by RefSeq, Aug 2015]

HPS1 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
Hermansky-Pudlak syndrome with pulmonary fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HPS1 links:

ENSG00000289758 (HGNC:):

ENSG00000289758 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 10-98424305-C-A is Benign according to our data. Variant chr10-98424305-C-A is described in ClinVar as Benign. ClinVar VariationId is 163664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5 link	c.1397+8G>T		splice_region_variant, intron_variant	Intron 14 of 19	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9 link	c.1397+8G>T		splice_region_variant, intron_variant	Intron 14 of 19	1	NM_000195.5	ENSP00000355310.4		Q92902-1
ENSG00000289758	ENST00000699159.1 link	n.*756+8G>T		splice_region_variant, intron_variant	Intron 13 of 23			ENSP00000514167.1		A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33210

AN:

151912

Hom.:

4108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.262

Gnomad AMR

AF:

0.281

Gnomad ASJ

AF:

0.311

Gnomad EAS

AF:

0.369

Gnomad SAS

AF:

0.396

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.236

Gnomad OTH

AF:

0.216

GnomAD2 exomes

AF:

0.264

AC:

64703

AN:

245248

AF XY:

0.270

show subpopulations

Gnomad AFR exome

AF:

0.113

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.310

Gnomad EAS exome

AF:

0.345

Gnomad FIN exome

AF:

0.224

Gnomad NFE exome

AF:

0.231

Gnomad OTH exome

AF:

0.256

GnomAD4 exome

AF:

0.247

AC:

359167

AN:

1452978

Hom.:

46925

Cov.:

AF XY:

0.252

AC XY:

182402

AN XY:

722744

show subpopulations

African (AFR)

AF:

0.117

AC:

3898

AN:

33354

American (AMR)

AF:

0.297

AC:

13116

AN:

44196

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

8040

AN:

25904

East Asian (EAS)

AF:

0.365

AC:

14442

AN:

39564

South Asian (SAS)

AF:

0.404

AC:

34461

AN:

85232

European-Finnish (FIN)

AF:

0.230

AC:

12207

AN:

53058

Middle Eastern (MID)

AF:

0.303

AC:

1743

AN:

5758

European-Non Finnish (NFE)

AF:

0.232

AC:

256021

AN:

1105780

Other (OTH)

AF:

0.253

AC:

15239

AN:

60132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

13420

26839

40259

53678

67098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8860

17720

26580

35440

44300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.218

AC:

33219

AN:

152034

Hom.:

4112

Cov.:

AF XY:

0.223

AC XY:

16574

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.118

AC:

4913

AN:

41538

American (AMR)

AF:

0.281

AC:

4300

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.311

AC:

1077

AN:

3462

East Asian (EAS)

AF:

0.369

AC:

1895

AN:

5136

South Asian (SAS)

AF:

0.396

AC:

1908

AN:

4822

European-Finnish (FIN)

AF:

0.223

AC:

2357

AN:

10586

Middle Eastern (MID)

AF:

0.229

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.236

AC:

16013

AN:

67904

Other (OTH)

AF:

0.214

AC:

451

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1287

2574

3860

5147

6434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.223

Hom.:

1777

Bravo

AF:

0.214

Asia WGS

AF:

0.332

AC:

1153

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

1397+8G>T in intron 14 of HPS1: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 20.4% (1753/8600) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs2296433). -

Feb 26, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Dec 17, 2023

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

- -

Apr 07, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome 1

Benign:2

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.79

CADD

Benign

(source)

DANN

Benign

0.52

PhyloP100

0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00062

dbscSNV1_RF

Benign

0.012

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over