rs201227603

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_032383.5(HPS3):c.1163+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,612,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

HPS3
NM_032383.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 8.03

Publications

7 publications found

Variant links:

Genes affected

HPS3 (HGNC:15597): (HPS3 biogenesis of lysosomal organelles complex 2 subunit 1) This gene encodes a protein containing a potential clathrin-binding motif, consensus dileucine signals, and tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. The encoded protein may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 3. [provided by RefSeq, Apr 2015]

HPS3 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
Hermansky-Pudlak syndrome without pulmonary fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HPS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.2, offset of 28, new splice context is: cctGTgagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-149145547-G-A is Pathogenic according to our data. Variant chr3-149145547-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS3	NM_032383.5 link	c.1163+1G>A		splice_donor_variant, intron_variant	Intron 5 of 16	ENST00000296051.7	NP_115759.2	Q969F9-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HPS3	ENST00000296051.7 link	c.1163+1G>A	splice_donor_variant, intron_variant	Intron 5 of 16	1	NM_032383.5	ENSP00000296051.2	Q969F9-1
HPS3	ENST00000460120.5 link	c.668+1G>A	splice_donor_variant, intron_variant	Intron 4 of 15	2		ENSP00000418230.1	G5E9V4
HPS3	ENST00000462030.5 link	n.1762+1G>A	splice_donor_variant, intron_variant	Intron 5 of 6	2
HPS3	ENST00000486530.1 link	n.1196+1G>A	splice_donor_variant, intron_variant	Intron 5 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000796

AC:

AN:

251320

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1460762

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726740

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33448

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00172

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1110992

Other (OTH)

AF:

0.000166

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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:

0.0000526

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000798

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 3

Pathogenic:4Other:1

Nov 03, 2021

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_032383.3(HPS3):c.1163+1G>A is a canonical splice variant classified as pathogenic in the context of Hermansky-Pudlak syndrome type 3. Please note that c.1163+1G>A may be associated with a mild form of the disease. c.1163+1G>A has been observed in cases with relevant disease (PMID: 11590544). Functional assessments of this variant are available in the literature (PMID: 11590544). c.1163+1G>A has been observed in population frequency databases (gnomAD: ASJ 0.16%). In summary, NM_032383.3(HPS3):c.1163+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, has functional support for pathogenicity, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Nov 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 25, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome

Pathogenic:3

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 08, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1163+1G>A variant, also known as c.1303+1G>A, in HPS3 has been reported in the homozygous state in 3 individuals with Hermansky Pudlak syndrome type 3 and in the compound heterozygous state with other splice site variants in 2 individ uals with Hermansky Pudlak syndrome type 3, all of whom had Ashkenazi Jewish anc estry (Huizing 2001). It has also been identified in 0.17% (17/10150) of Ashkena zi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence. Stud ies have demonstrated that this variant cases skipping of exon 5, resulting in a premature translational stop at codon 350, which is predicted to produce a trun cated or absent protein (Huizing 2001). Loss of function of the HPS3 gene is an established disease mechanism in Hermansky Pudlak syndrome type 3, which is a mi lder form of Hermansky Pudlak syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hermansky Pudlak syndrome . ACMG/AMP Criteria applied: PVS1, PM3_Strong, PS3_Supporting. -

May 19, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HPS3 c.1163+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of HPS3 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 8e-05 in 251320 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HPS3 causing Hermansky-Pudlak Syndrome (8e-05 vs 0.00055), allowing no conclusion about variant significance. c.1163+1G>A has been observed in multiple individuals affected with Hermansky-Pudlak Syndrome (Huizing_2001). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 11590544). ClinVar contains an entry for this variant (Variation ID: 4609). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 5 of the HPS3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs201227603, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. Disruption of this splice site has been observed in individuals with Hermansky-Pudlak syndrome (HPS) (PMID: 11590544). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 11590544). This variant is also known as 1303+1G>A. ClinVar contains an entry for this variant (Variation ID: 4609). Studies have shown that disruption of this splice site results in skipping of exon 5, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 11590544). For these reasons, this variant has been classified as Pathogenic. -

Feb 16, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

HPS3-related disorder

Pathogenic:1

Apr 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The HPS3 c.1163+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also referred to as c.1303+1G>A in the literature, results in skipping of exon 5 during mRNA splicing (Huizing et al. 2001. PubMed ID: 11590544) and has been reported in the homozygous or compound heterozygous state in individuals of Ashkenazi Jewish ancestry with Hermansky-Pudlak syndrome (Huizing et al. 2001. PubMed ID: 11590544; Marek-Yagel et al. 2022. PubMed ID: 36046236). This variant is reported in 0.15% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Variants that disrupt the consensus splice donor site in HPS3 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

PhyloP100

8.0

GERP RS

5.5

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.57

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.57

Position offset: -1

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