rs2296435

Positions:

• chr10-98422528-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000195.5(HPS1):​c.1599-15A>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.670

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]

ACMG classification

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	UniProt
HPS1	NM_000195.5	c.1599-15A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.1599-15A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000195.5	P1

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

GnomAD3 exomes AF: 0.271 AC: 67930 AN: 250900 Hom.: 9965 AF XY: 0.277 AC XY: 37602 AN XY: 135766

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

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.: 33 AF XY: 0.228 AC XY: 16935 AN XY: 74370

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:7

Revision: criteria provided, multiple submitters, no conflicts

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:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hermansky-Pudlak syndrome 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
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

Other links and lift over

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