10-98424306-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000195.5(HPS1):c.1397+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,605,454 control chromosomes in the GnomAD database, including 51,118 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 (4114 hom., cov: 33)
  • Exomes 𝑓: 0.25 (47004 hom.)
• Consequence: HPS1 NM_000195.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001668
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.287

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-98424306-C-G is Benign according to our data. Variant chr10-98424306-C-G is described in ClinVar as [Benign]. Clinvar id is 163665.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/exons	MANE	UniProt
HPS1	NM_000195.5	c.1397+7G>C		splice_region_variant, intron_variant		ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.1397+7G>C		splice_region_variant, intron_variant		1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33221 AN: 151900 Hom.: 4110 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.261

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: 0.215

GnomAD3 exomes AF: 0.264 AC: 64776 AN: 245288 Hom.: 9022 AF XY: 0.270 AC XY: 35796 AN XY: 132402

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 SAS exome AF: 0.394

Gnomad FIN exome AF: 0.224

Gnomad NFE exome AF: 0.231

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.247 AC: 359608 AN: 1453432 Hom.: 47004 Cov.: 32 AF XY: 0.253 AC XY: 182609 AN XY: 722910

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.297

Gnomad4 ASJ exome AF: 0.311

Gnomad4 EAS exome AF: 0.365

Gnomad4 SAS exome AF: 0.404

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.232

Gnomad4 OTH exome AF: 0.254

GnomAD4 genome AF: 0.219 AC: 33230 AN: 152022 Hom.: 4114 Cov.: 33 AF XY: 0.223 AC XY: 16577 AN XY: 74310

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.282

Gnomad4 ASJ AF: 0.311

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.395

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.236

Gnomad4 OTH AF: 0.214

Alfa AF: 0.236 Hom.: 1440

Bravo AF: 0.214

Asia WGS AF: 0.332 AC: 1153 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	1397+7G>C 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 20.5% (1763/8600) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs2296432). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	- -

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	Aug 10, 2021	- -

Hermansky-Pudlak syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	10
Dann	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.14		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: rs2296432; hg19: chr10-100184063; COSMIC: COSV57267562; COSMIC: COSV57267562;