rs58548334

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.98

Publications

11 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 163667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

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
HPS1	NM_000195.5	MANE Select	c.11T>C	p.Val4Ala	missense	Exon 3 of 20	NP_000186.2
HPS1	NM_001322476.2		c.11T>C	p.Val4Ala	missense	Exon 3 of 20	NP_001309405.1
HPS1	NM_001322477.2		c.11T>C	p.Val4Ala	missense	Exon 3 of 20	NP_001309406.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HPS1	ENST00000361490.9	TSL:1 MANE Select	c.11T>C	p.Val4Ala	missense	Exon 3 of 20	ENSP00000355310.4
HPS1	ENST00000338546.9	TSL:1	c.11T>C	p.Val4Ala	missense	Exon 3 of 10	ENSP00000343638.5
HPS1	ENST00000467246.5	TSL:1	n.11T>C		non_coding_transcript_exon	Exon 3 of 19	ENSP00000514163.1

Frequencies

GnomAD3 genomes

AF:

0.0362

AC:

5507

AN:

151990

Hom.:

124

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0313

AC:

7864

AN:

251482

AF XY:

0.0323

show subpopulations

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 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.:

AF XY:

0.0258

AC XY:

18749

AN XY:

726898

show subpopulations

African (AFR)

AF:

0.0617

AC:

2065

AN:

33452

American (AMR)

AF:

0.0151

AC:

674

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0372

AC:

972

AN:

26132

East Asian (EAS)

AF:

0.00990

AC:

393

AN:

39690

South Asian (SAS)

AF:

0.0497

AC:

4282

AN:

86220

European-Finnish (FIN)

AF:

0.0511

AC:

2732

AN:

53414

Middle Eastern (MID)

AF:

0.0536

AC:

309

AN:

5766

European-Non Finnish (NFE)

AF:

0.0209

AC:

23211

AN:

1111308

Other (OTH)

AF:

0.0300

AC:

1814

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

1909

3818

5726

7635

9544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

862

1724

2586

3448

4310

<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:

0.0363

AC:

5516

AN:

152108

Hom.:

124

Cov.:

AF XY:

0.0376

AC XY:

2797

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0608

AC:

2524

AN:

41488

American (AMR)

AF:

0.0192

AC:

294

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0380

AC:

132

AN:

3472

East Asian (EAS)

AF:

0.0110

AC:

AN:

5162

South Asian (SAS)

AF:

0.0548

AC:

263

AN:

4798

European-Finnish (FIN)

AF:

0.0477

AC:

506

AN:

10598

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0245

AC:

1669

AN:

67984

Other (OTH)

AF:

0.0280

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

268

537

805

1074

1342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0276

Hom.:

205

Bravo

AF:

0.0324

TwinsUK

AF:

0.0191

AC:

ALSPAC

AF:

0.0182

AC:

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Hermansky-Pudlak syndrome (1)

Hermansky-Pudlak syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.5

PhyloP100

8.0

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.18

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0050

Polyphen

0.97

Vest4

0.21

MPC

0.45

ClinPred

0.020

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.55

Mutation Taster

=82/18

polymorphism (auto)

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over