rs701801

Positions:

• chr10-98417112-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000195.5(HPS1):​c.*452G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 156,666 control chromosomes in the GnomAD database, including 13,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.39 (12845 hom., cov: 33)
  • Exomes 𝑓: 0.27 (217 hom.)
• Consequence: HPS1 NM_000195.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.26

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-98417112-C-T is Benign according to our data. Variant chr10-98417112-C-T is described in ClinVar as [Benign]. Clinvar id is 298329.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5	c.*452G>A		3_prime_UTR_variant	20/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.*452G>A		3_prime_UTR_variant	20/20	1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59463 AN: 151772 Hom.: 12802 Cov.: 33

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.379

GnomAD4 exome AF: 0.269 AC: 1287 AN: 4776 Hom.: 217 Cov.: 0 AF XY: 0.281 AC XY: 665 AN XY: 2368

Gnomad4 AFR exome AF: 0.482

Gnomad4 AMR exome AF: 0.386

Gnomad4 ASJ exome AF: 0.425

Gnomad4 EAS exome AF: 0.325

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.241

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.246

GnomAD4 genome AF: 0.392 AC: 59559 AN: 151890 Hom.: 12845 Cov.: 33 AF XY: 0.395 AC XY: 29336 AN XY: 74228

Gnomad4 AFR AF: 0.570

Gnomad4 AMR AF: 0.411

Gnomad4 ASJ AF: 0.407

Gnomad4 EAS AF: 0.486

Gnomad4 SAS AF: 0.396

Gnomad4 FIN AF: 0.276

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.376

Alfa AF: 0.316 Hom.: 7762

Bravo AF: 0.406

Asia WGS AF: 0.430 AC: 1494 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome 1 Benign:1

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	-0.88
CADD	Benign	0.058
DANN	Benign	0.63

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: rs701801; hg19: chr10-100176869;