chr10-98423758-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000195.5(HPS1):c.1527C>G(p.Leu509Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,614,126 control chromosomes in the GnomAD database, including 405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L509L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 36 hom., cov: 32)

Exomes 𝑓: 0.011 ( 369 hom. )

Consequence

HPS1
NM_000195.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.50

Publications

10 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 10-98423758-G-C is Benign according to our data. Variant chr10-98423758-G-C is described in ClinVar as Benign. ClinVar VariationId is 255501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.5 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5 link	c.1527C>G	p.Leu509Leu	synonymous_variant	Exon 15 of 20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HPS1	ENST00000361490.9 link	c.1527C>G	p.Leu509Leu	synonymous_variant	Exon 15 of 20	1	NM_000195.5	ENSP00000355310.4	Q92902-1
ENSG00000289758	ENST00000699159.1 link	n.*886C>G		non_coding_transcript_exon_variant	Exon 14 of 24			ENSP00000514167.1	A0A8V8TP71
ENSG00000289758	ENST00000699159.1 link	n.*886C>G		3_prime_UTR_variant	Exon 14 of 24			ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2310

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0269

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00883

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0374

Gnomad SAS

AF:

0.0836

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00619

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0168

AC:

4212

AN:

251230

AF XY:

0.0191

show subpopulations

Gnomad AFR exome

AF:

0.0278

Gnomad AMR exome

AF:

0.00457

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.0393

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00536

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.0111

AC:

16191

AN:

1461784

Hom.:

369

Cov.:

AF XY:

0.0128

AC XY:

9282

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.0308

AC:

1031

AN:

33480

American (AMR)

AF:

0.00478

AC:

214

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0269

AC:

1066

AN:

39700

South Asian (SAS)

AF:

0.0688

AC:

5933

AN:

86250

European-Finnish (FIN)

AF:

0.000825

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00992

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00625

AC:

6948

AN:

1112010

Other (OTH)

AF:

0.0147

AC:

888

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1029

2059

3088

4118

5147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

350

700

1050

1400

1750

<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:

0.0152

AC:

2308

AN:

152342

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1168

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0268

AC:

1114

AN:

41590

American (AMR)

AF:

0.00882

AC:

135

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0373

AC:

193

AN:

5178

South Asian (SAS)

AF:

0.0835

AC:

403

AN:

4828

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00619

AC:

421

AN:

68022

Other (OTH)

AF:

0.0147

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

126

252

377

503

629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.00807

Hom.:

Bravo

AF:

0.0144

Asia WGS

AF:

0.0700

AC:

244

AN:

3478

EpiCase

AF:

0.00545

EpiControl

AF:

0.00581

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome

Benign:1

Nov 26, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

-0.59

CADD

Benign

5.2

(source)

DANN

Benign

0.55

PhyloP100

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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