rs58548334

Positions:

• chr10-98443230-A-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.11T>C​(p.Val4Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,613,178 control chromosomes in the GnomAD database, including 791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.036 (124 hom., cov: 32)
  • Exomes 𝑓: 0.025 (667 hom.)
• Consequence: HPS1 NM_000195.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.98

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 (MetaRNN=0.004116535).
• BP6: Variant 10-98443230-A-G is Benign according to our data. Variant chr10-98443230-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 163667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98443230-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5	c.11T>C	p.Val4Ala	missense_variant	3/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.11T>C	p.Val4Ala	missense_variant	3/20	1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.0362 AC: 5507 AN: 151990 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0606

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0554

Gnomad FIN AF: 0.0477

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0283

GnomAD3 exomes AF: 0.0313 AC: 7864 AN: 251482 Hom.: 175 AF XY: 0.0323 AC XY: 4390 AN XY: 135912

Gnomad AFR exome AF: 0.0615

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.0378

Gnomad EAS exome AF: 0.00827

Gnomad SAS exome AF: 0.0517

Gnomad FIN exome AF: 0.0499

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0296

GnomAD4 exome AF: 0.0249 AC: 36452 AN: 1461070 Hom.: 667 Cov.: 30 AF XY: 0.0258 AC XY: 18749 AN XY: 726898

Gnomad4 AFR exome AF: 0.0617

Gnomad4 AMR exome AF: 0.0151

Gnomad4 ASJ exome AF: 0.0372

Gnomad4 EAS exome AF: 0.00990

Gnomad4 SAS exome AF: 0.0497

Gnomad4 FIN exome AF: 0.0511

Gnomad4 NFE exome AF: 0.0209

Gnomad4 OTH exome AF: 0.0300

GnomAD4 genome AF: 0.0363 AC: 5516 AN: 152108 Hom.: 124 Cov.: 32 AF XY: 0.0376 AC XY: 2797 AN XY: 74372

Gnomad4 AFR AF: 0.0608

Gnomad4 AMR AF: 0.0192

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.0548

Gnomad4 FIN AF: 0.0477

Gnomad4 NFE AF: 0.0245

Gnomad4 OTH AF: 0.0280

Alfa AF: 0.0258 Hom.: 66

Bravo AF: 0.0324

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.0629 AC: 277

ESP6500EA AF: 0.0215 AC: 185

ExAC AF: 0.0333 AC: 4037

Asia WGS AF: 0.0390 AC: 136 AN: 3478

EpiCase AF: 0.0245

EpiControl AF: 0.0220

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely 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	Val4Ala in exon 3 of HPS1: This variant is not expected to have clinical signifi cance because it has been identified in 6.3% (277/4406) of African American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS; dbSNP rs58548334). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hermansky-Pudlak syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 26, 2021

- -

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
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0041	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.5	M;M;M;M
MutationTaster	Benign	0.79	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.7	D;D;.;N
REVEL	Benign	0.18
Sift	Uncertain	0.011	D;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.97	D;D;D;P
Vest4		0.21
MPC		0.45
ClinPred		0.020	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.55

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: rs58548334; hg19: chr10-100202987; COSMIC: COSV57269581;