10-98427229-TG-TGG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_Very_Strong

The NM_000195.5(HPS1):c.972dupC(p.Met325HisfsTer128) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,534,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000713081: "In vitro functional studies provide some evidence that the p.Met325fs variant may impact protein function (Gonzalez-Conejero 2003)."" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P324P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

HPS1
NM_000195.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 0.721

Publications

18 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: Pathogenic. The variant received 20 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000713081: "In vitro functional studies provide some evidence that the p.Met325fs variant may impact protein function (Gonzalez-Conejero 2003)."; SCV002097069: "In vitro functional studies provide some evidence that the p.Met325fs variant may slightly impact protein function." PMID:14510955

PP5

Variant 10-98427229-T-TG is Pathogenic according to our data. Variant chr10-98427229-T-TG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.972dupC	p.Met325HisfsTer128	frameshift	Exon 11 of 20	NP_000186.2
HPS1	NM_001322476.2		c.972dupC	p.Met325HisfsTer128	frameshift	Exon 11 of 20	NP_001309405.1	Q92902-1
HPS1	NM_001322477.2		c.972dupC	p.Met325HisfsTer128	frameshift	Exon 11 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.972dupC	p.Met325HisfsTer128	frameshift	Exon 11 of 20	ENSP00000355310.4	Q92902-1
HPS1	ENST00000467246.5	TSL:1	n.*331dupC		non_coding_transcript_exon	Exon 10 of 19	ENSP00000514163.1	A0A8V8TP71
ENSG00000289758	ENST00000699159.1		n.*331dupC		non_coding_transcript_exon	Exon 10 of 24	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000291

AC:

AN:

144354

AF XY:

0.000237

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000265

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000961

Gnomad FIN exome

AF:

0.000286

Gnomad NFE exome

AF:

0.000428

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000348

AC:

481

AN:

1382068

Hom.:

Cov.:

AF XY:

0.000333

AC XY:

227

AN XY:

682128

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000193

AC:

AN:

31010

American (AMR)

AF:

0.000198

AC:

AN:

35308

Ashkenazi Jewish (ASJ)

AF:

0.0000804

AC:

AN:

24888

East Asian (EAS)

AF:

0.000113

AC:

AN:

35364

South Asian (SAS)

AF:

0.000191

AC:

AN:

78354

European-Finnish (FIN)

AF:

0.00217

AC:

105

AN:

48314

Middle Eastern (MID)

AF:

0.000354

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.000308

AC:

328

AN:

1065960

Other (OTH)

AF:

0.000210

AC:

AN:

57228

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.387

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000158

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41508

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67916

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.00116

Hom.:

Bravo

AF:

0.000155

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hermansky-Pudlak syndrome 1 (14)

Hermansky-Pudlak syndrome (5)

not provided (2)

HPS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.72

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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