rs11539873

chr10-98435373-G-Achr10-98435373-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000195.5(HPS1):c.297C>T(p.Thr99=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0603 in 1,613,862 control chromosomes in the GnomAD database, including 3,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (250 hom., cov: 32)
  • Exomes 𝑓: 0.061 (2939 hom.)
• Consequence: HPS1 NM_000195.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.47

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-98435373-G-A is Benign according to our data. Variant chr10-98435373-G-A is described in ClinVar as [Benign]. Clinvar id is 163666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5	c.297C>T	p.Thr99=	synonymous_variant	5/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.297C>T	p.Thr99=	synonymous_variant	5/20	1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 7725 AN: 152036 Hom.: 250 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0541

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.0677

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0610

Gnomad OTH AF: 0.0707

GnomAD3 exomes AF: 0.0656 AC: 16495 AN: 251304 Hom.: 668 AF XY: 0.0640 AC XY: 8695 AN XY: 135846

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.0662

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.145

Gnomad SAS exome AF: 0.0324

Gnomad FIN exome AF: 0.0680

Gnomad NFE exome AF: 0.0641

Gnomad OTH exome AF: 0.0697

GnomAD4 exome AF: 0.0613 AC: 89555 AN: 1461708 Hom.: 2939 Cov.: 32 AF XY: 0.0606 AC XY: 44093 AN XY: 727160

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.0649

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.0336

Gnomad4 FIN exome AF: 0.0683

Gnomad4 NFE exome AF: 0.0605

Gnomad4 OTH exome AF: 0.0684

GnomAD4 genome AF: 0.0507 AC: 7719 AN: 152154 Hom.: 250 Cov.: 32 AF XY: 0.0526 AC XY: 3914 AN XY: 74368

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.0541

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.0362

Gnomad4 FIN AF: 0.0677

Gnomad4 NFE AF: 0.0610

Gnomad4 OTH AF: 0.0691

Alfa AF: 0.0587 Hom.: 199

Bravo AF: 0.0497

Asia WGS AF: 0.0660 AC: 230 AN: 3478

EpiCase AF: 0.0664

EpiControl AF: 0.0672

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr99Thr in exon 5 of HPS1: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 6.0% (512/8600) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11539873). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 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 12, 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	- -

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	-0.88
Cadd	Benign	0.023
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs11539873; hg19: chr10-100195130; COSMIC: COSV57266384; COSMIC: COSV57266384;