rs701801

Variant names:

Variant summary

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

The ENST00000467246.5(HPS1):n.*1914G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 156,666 control chromosomes in the GnomAD database, including 13,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12845 hom., cov: 33)

Exomes 𝑓: 0.27 ( 217 hom. )

Consequence

HPS1
ENST00000467246.5 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -5.26

Publications

33 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 (BayesDel_noAF=-0.88).

BP6

Variant 10-98417112-C-T is Benign according to our data. Variant chr10-98417112-C-T is described in ClinVar as Benign. ClinVar VariationId is 298329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5 link	c.*452G>A		3_prime_UTR_variant	Exon 20 of 20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENSG00000289758	ENST00000699159.1 link	n.*1434G>A	non_coding_transcript_exon_variant	Exon 20 of 24			ENSP00000514167.1	A0A8V8TP71
HPS1	ENST00000361490.9 link	c.*452G>A	3_prime_UTR_variant	Exon 20 of 20	1	NM_000195.5	ENSP00000355310.4	Q92902-1
ENSG00000289758	ENST00000699159.1 link	n.*1434G>A	3_prime_UTR_variant	Exon 20 of 24			ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.392

AC:

59463

AN:

151772

Hom.:

12802

Cov.:

show subpopulations

Gnomad AFR

AF:

0.569

Gnomad AMI

AF:

0.309

Gnomad AMR

AF:

0.410

Gnomad ASJ

AF:

0.407

Gnomad EAS

AF:

0.485

Gnomad SAS

AF:

0.397

Gnomad FIN

AF:

0.276

Gnomad MID

AF:

0.350

Gnomad NFE

AF:

0.292

Gnomad OTH

AF:

0.379

GnomAD4 exome

AF:

0.269

AC:

1287

AN:

4776

Hom.:

217

Cov.:

AF XY:

0.281

AC XY:

665

AN XY:

2368

show subpopulations

African (AFR)

AF:

0.482

AC:

AN:

American (AMR)

AF:

0.386

AC:

187

AN:

484

Ashkenazi Jewish (ASJ)

AF:

0.425

AC:

AN:

East Asian (EAS)

AF:

0.325

AC:

AN:

114

South Asian (SAS)

AF:

0.372

AC:

AN:

250

European-Finnish (FIN)

AF:

0.241

AC:

AN:

174

Middle Eastern (MID)

AF:

0.250

AC:

AN:

European-Non Finnish (NFE)

AF:

0.239

AC:

809

AN:

3382

Other (OTH)

AF:

0.246

AC:

AN:

232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

134

178

223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.392

AC:

59559

AN:

151890

Hom.:

12845

Cov.:

AF XY:

0.395

AC XY:

29336

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.570

AC:

23590

AN:

41414

American (AMR)

AF:

0.411

AC:

6276

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.407

AC:

1411

AN:

3468

East Asian (EAS)

AF:

0.486

AC:

2492

AN:

5132

South Asian (SAS)

AF:

0.396

AC:

1906

AN:

4812

European-Finnish (FIN)

AF:

0.276

AC:

2911

AN:

10564

Middle Eastern (MID)

AF:

0.353

AC:

103

AN:

292

European-Non Finnish (NFE)

AF:

0.291

AC:

19795

AN:

67910

Other (OTH)

AF:

0.376

AC:

794

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1777

3554

5332

7109

8886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

574

1148

1722

2296

2870

<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:

0.327

Hom.:

11041

Bravo

AF:

0.406

Asia WGS

AF:

0.430

AC:

1494

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hermansky-Pudlak syndrome 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.058

(source)

DANN

Benign

0.63

PhyloP100

-5.3

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over