rs139061260

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_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. 13/22 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.89

Publications

8 publications found

Variant links:

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]

HPS1 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
Hermansky-Pudlak syndrome with pulmonary fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HPS1 links:

ENSG00000289758 (HGNC:):

ENSG00000289758 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 VariationId is 21100.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000195.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS1	NM_000195.5	MANE Select	c.1888G>A	p.Val630Ile	missense	Exon 19 of 20	NP_000186.2
HPS1	NM_001322476.2		c.1888G>A	p.Val630Ile	missense	Exon 19 of 20	NP_001309405.1	Q92902-1
HPS1	NM_001322477.2		c.1888G>A	p.Val630Ile	missense	Exon 19 of 20	NP_001309406.1	Q92902-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS1	ENST00000361490.9	TSL:1 MANE Select	c.1888G>A	p.Val630Ile	missense	Exon 19 of 20	ENSP00000355310.4	Q92902-1
HPS1	ENST00000467246.5	TSL:1	n.*1247G>A		non_coding_transcript_exon	Exon 18 of 19	ENSP00000514163.1	A0A8V8TP71
ENSG00000289758	ENST00000699159.1		n.*1247G>A		non_coding_transcript_exon	Exon 18 of 24	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152172

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00130

AC:

323

AN:

248998

AF XY:

0.00129

show subpopulations

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 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.:

Cov.:

AF XY:

0.00120

AC XY:

873

AN XY:

724548

show subpopulations

African (AFR)

AF:

0.000569

AC:

AN:

33376

American (AMR)

AF:

0.00113

AC:

AN:

44404

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

25970

East Asian (EAS)

AF:

0.000101

AC:

AN:

39570

South Asian (SAS)

AF:

0.000105

AC:

AN:

85554

European-Finnish (FIN)

AF:

0.00203

AC:

108

AN:

53298

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00130

AC:

1444

AN:

1108908

Other (OTH)

AF:

0.00135

AC:

AN:

60216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

161

242

322

403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00135

AC:

205

AN:

152290

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41562

American (AMR)

AF:

0.000915

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00163

AC:

111

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.00114

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00129

AC:

157

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00127

EpiControl

AF:

0.00143

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Hermansky-Pudlak syndrome 1 (1)

HPS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.65

M_CAP

Benign

0.047

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.6

PhyloP100

2.9

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.54

REVEL

Benign

0.13

Sift

Uncertain

0.024

Sift4G

Uncertain

0.028

Vest4

0.32

MVP

0.31

MPC

0.57

ClinPred

0.025

GERP RS

3.7

Varity_R

0.043

gMVP

0.15

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over