rs281865082

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000195.5(HPS1):c.972delC(p.Met325TrpfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,535,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002067348: Functional studies have shown results that suggest a lack of function of the protein (PMID:21833017)." 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 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

HPS1
NM_000195.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O: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: SCV002067348: Functional studies have shown results that suggest a lack of function of the protein (PMID: 21833017).; SCV002097070: "In vitro functional studies provide some evidence that the p.Met325fs variant may impact protein function." PMID:9705234

PP5

Variant 10-98427229-TG-T is Pathogenic according to our data. Variant chr10-98427229-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5280.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.972delC	p.Met325TrpfsTer6	frameshift	Exon 11 of 20	NP_000186.2
HPS1	NM_001322476.2		c.972delC	p.Met325TrpfsTer6	frameshift	Exon 11 of 20	NP_001309405.1	Q92902-1
HPS1	NM_001322477.2		c.972delC	p.Met325TrpfsTer6	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.972delC	p.Met325TrpfsTer6	frameshift	Exon 11 of 20	ENSP00000355310.4	Q92902-1
HPS1	ENST00000467246.5	TSL:1	n.*331delC		non_coding_transcript_exon	Exon 10 of 19	ENSP00000514163.1	A0A8V8TP71
ENSG00000289758	ENST00000699159.1		n.*331delC		non_coding_transcript_exon	Exon 10 of 24	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000166

AC:

AN:

144354

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000132

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000288

Gnomad FIN exome

AF:

0.000857

Gnomad NFE exome

AF:

0.0000714

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000455

AC:

AN:

1383570

Hom.:

Cov.:

AF XY:

0.0000425

AC XY:

AN XY:

682764

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

31044

American (AMR)

AF:

0.0000566

AC:

AN:

35310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24906

East Asian (EAS)

AF:

0.0000848

AC:

AN:

35386

South Asian (SAS)

AF:

0.0000383

AC:

AN:

78382

European-Finnish (FIN)

AF:

0.000578

AC:

AN:

48406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1067228

Other (OTH)

AF:

0.00

AC:

AN:

57262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000125

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41508

American (AMR)

AF:

0.00

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:

0.000472

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67916

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.0000567

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hermansky-Pudlak syndrome 1 (8)

Hermansky-Pudlak syndrome (2)

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)

0.030

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