rs2296435

Variant names:

• chr10-98422528-T-C
• rs2296435
• NM_000195.5:c.1599-15A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.670
• Publications: 19 publications found

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

ENSG00000289758 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000195.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	NM_000195.5	MANE Select	c.1599-15A>G		intron	N/A	NP_000186.2
	HPS1	NM_001322476.2		c.1599-15A>G		intron	N/A	NP_001309405.1
	HPS1	NM_001322477.2		c.1599-15A>G		intron	N/A	NP_001309406.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.1599-15A>G		intron	N/A	ENSP00000355310.4
	HPS1	ENST00000467246.5	TSL:1	n.*958-15A>G		intron	N/A	ENSP00000514163.1
	ENSG00000289758	ENST00000699159.1		n.*958-15A>G		intron	N/A	ENSP00000514167.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 33978 AN: 152018 Hom.: 4242 Cov.: 33

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

GnomAD2 exomes AF: 0.271 AC: 67930 AN: 250900 AF XY: 0.277

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 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.: 36 AF XY: 0.254 AC XY: 184776 AN XY: 726354

African (AFR) AF: 0.135 AC: 4513 AN: 33462

American (AMR) AF: 0.303 AC: 13547 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 8155 AN: 26120

East Asian (EAS) AF: 0.362 AC: 14344 AN: 39678

South Asian (SAS) AF: 0.405 AC: 34936 AN: 86206

European-Finnish (FIN) AF: 0.231 AC: 12256 AN: 52972

Middle Eastern (MID) AF: 0.305 AC: 1759 AN: 5766

European-Non Finnish (NFE) AF: 0.233 AC: 258923 AN: 1110664

Other (OTH) AF: 0.255 AC: 15357 AN: 60322

GnomAD4 genome AF: 0.223 AC: 33993 AN: 152136 Hom.: 4245 Cov.: 33 AF XY: 0.228 AC XY: 16935 AN XY: 74370

African (AFR) AF: 0.135 AC: 5620 AN: 41528

American (AMR) AF: 0.283 AC: 4327 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1080 AN: 3464

East Asian (EAS) AF: 0.356 AC: 1832 AN: 5140

South Asian (SAS) AF: 0.394 AC: 1895 AN: 4814

European-Finnish (FIN) AF: 0.223 AC: 2364 AN: 10588

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16105 AN: 67982

Other (OTH) AF: 0.218 AC: 461 AN: 2116

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

Submissions by phenotype

not specified Benign:3

Feb 26, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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

Apr 07, 2019

GeneDx

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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.

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.79
PhyloP100		0.67
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2296435; hg19: chr10-100182285; COSMIC: COSV57267541; COSMIC: COSV57267541;