rs139061260

Positions:

• chr10-98418227-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_000195.5(HPS1):​c.1888G>A​(p.Val630Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,609,336 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: HPS1 NM_000195.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.89

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]

ENSG00000289758 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017379493).
• BP6: Variant 10-98418227-C-T is Benign according to our data. Variant chr10-98418227-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21100.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr10-98418227-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS1	NM_000195.5	c.1888G>A	p.Val630Ile	missense_variant	19/20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9	c.1888G>A	p.Val630Ile	missense_variant	19/20	1	NM_000195.5	ENSP00000355310.4
ENSG00000289758	ENST00000699159.1	n.*1247G>A		non_coding_transcript_exon_variant	18/24			ENSP00000514167.1
ENSG00000289758	ENST00000699159.1	n.*1247G>A		3_prime_UTR_variant	18/24			ENSP00000514167.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00130 AC: 323 AN: 248998 Hom.: 0 AF XY: 0.00129 AC XY: 174 AN XY: 134506

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.00354

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000199

Gnomad FIN exome AF: 0.00209

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00125 AC: 1818 AN: 1457046 Hom.: 2 Cov.: 29 AF XY: 0.00120 AC XY: 873 AN XY: 724548

Gnomad4 AFR exome AF: 0.000569

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.00374

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00203

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.00135

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74452

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00114

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00129 AC: 157

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00127

EpiControl AF: 0.00143

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 23, 2023	Variant summary: HPS1 c.1888G>A (p.Val630Ile) results in a conservative amino acid change located in the FUZ/MON1/HPS1, third Longin domain (IPR043970) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 248998 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HPS1 causing Hermansky-Pudlak Syndrome phenotype (0.00096), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1888G>A has been reported in the literature in individuals affected with Hermansky-Pudlak Syndrome however in the presence of Pro324 frameshift indicating a benign role for this variant (Oh_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and cassified the variant as VUS (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 30, 2018	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2019	Reported in published literature in an individual with pulmonary fibrosis; however, additional clinical information and familial segregation was not provided (Stearman et al., 2019); Reported as a benign variant in published literature, however, supporting details regarding how this classification was determined were not provided (Shotelersuk et al., 1998; Huizing et al., 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12125811, 30985222, 9787100, 11208073) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Hermansky-Pudlak syndrome 1 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

HPS1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 07, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.65	.;.;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.6	M;M;M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.54	N;N;.
REVEL	Benign	0.13
Sift	Uncertain	0.024	D;D;.
Sift4G	Uncertain	0.028	D;D;D
Vest4		0.32
MVP		0.31
MPC		0.57
ClinPred		0.025	T
GERP RS		3.7
Varity_R		0.043
gMVP		0.15

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: rs139061260; hg19: chr10-100177984; COSMIC: COSV57266895; COSMIC: COSV57266895;