rs2296435

Positions:

chr10-98422528-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000195.5(HPS1):c.1599-15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,612,042 control chromosomes in the GnomAD database, including 52,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.22 ( 4245 hom., cov: 33)

Exomes 𝑓: 0.25 ( 47860 hom. )

Consequence

HPS1
NM_000195.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.670

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 links:

ENSG00000289758 (HGNC:):

ENSG00000289758 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 10-98422528-T-C is Benign according to our data. Variant chr10-98422528-T-C is described in ClinVar as [Benign]. Clinvar id is 167184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS1	NM_000195.5 linkuse as main transcript	c.1599-15A>G		intron_variant		ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9 linkuse as main transcript	c.1599-15A>G		intron_variant		1	NM_000195.5	ENSP00000355310.4		Q92902-1
ENSG00000289758	ENST00000699159.1 linkuse as main transcript	n.*958-15A>G		intron_variant				ENSP00000514167.1		A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.224

AC:

33978

AN:

152018

Hom.:

4242

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.263

Gnomad AMR

AF:

0.282

Gnomad ASJ

AF:

0.312

Gnomad EAS

AF:

0.357

Gnomad SAS

AF:

0.394

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.237

Gnomad OTH

AF:

0.219

GnomAD3 exomes

AF:

0.271

AC:

67930

AN:

250900

Hom.:

9965

AF XY:

0.277

AC XY:

37602

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.305

Gnomad ASJ exome

AF:

0.314

Gnomad EAS exome

AF:

0.339

Gnomad SAS exome

AF:

0.399

Gnomad FIN exome

AF:

0.228

Gnomad NFE exome

AF:

0.239

Gnomad OTH exome

AF:

0.257

GnomAD4 exome

AF:

0.249

AC:

363790

AN:

1459906

Hom.:

47860

Cov.:

AF XY:

0.254

AC XY:

184776

AN XY:

726354

show subpopulations

Gnomad4 AFR exome

AF:

0.135

Gnomad4 AMR exome

AF:

0.303

Gnomad4 ASJ exome

AF:

0.312

Gnomad4 EAS exome

AF:

0.362

Gnomad4 SAS exome

AF:

0.405

Gnomad4 FIN exome

AF:

0.231

Gnomad4 NFE exome

AF:

0.233

Gnomad4 OTH exome

AF:

0.255

GnomAD4 genome

AF:

0.223

AC:

33993

AN:

152136

Hom.:

4245

Cov.:

AF XY:

0.228

AC XY:

16935

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.135

Gnomad4 AMR

AF:

0.283

Gnomad4 ASJ

AF:

0.312

Gnomad4 EAS

AF:

0.356

Gnomad4 SAS

AF:

0.394

Gnomad4 FIN

AF:

0.223

Gnomad4 NFE

AF:

0.237

Gnomad4 OTH

AF:

0.218

Alfa

AF:

0.237

Hom.:

1106

Bravo

AF:

0.219

Asia WGS

AF:

0.330

AC:

1146

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	1599-15A>G in intron 16 of HPS1: This variant is not expected to have clinical s ignificance because it has been identified in 24.0% (2061/8600) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs2296435). -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hermansky-Pudlak syndrome 1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.79

BranchPoint Hunter

3.0

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