NM_032383.5:c.970+7A>G

Variant names:

Variant summary

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

The NM_032383.5(HPS3):c.970+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,606,870 control chromosomes in the GnomAD database, including 1,367 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 74 hom., cov: 31)

Exomes 𝑓: 0.039 ( 1293 hom. )

Consequence

HPS3
NM_032383.5 splice_region, intron

Scores

Splicing: ADA: 0.000008553

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.35

Publications

5 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 3-149141387-A-G is Benign according to our data. Variant chr3-149141387-A-G is described in ClinVar as Benign. ClinVar VariationId is 178776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS3	NM_032383.5 link	c.970+7A>G		splice_region_variant, intron_variant	Intron 4 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.970+7A>G	splice_region_variant, intron_variant	Intron 4 of 16	1	NM_032383.5	ENSP00000296051.2	Q969F9-1
HPS3	ENST00000460120.5 link	c.475+7A>G	splice_region_variant, intron_variant	Intron 3 of 15	2		ENSP00000418230.1	G5E9V4
HPS3	ENST00000462030.5 link	n.1569+7A>G	splice_region_variant, intron_variant	Intron 4 of 6	2
HPS3	ENST00000486530.1 link	n.1003+7A>G	splice_region_variant, intron_variant	Intron 4 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0270

AC:

4103

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00908

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0178

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0634

Gnomad FIN

AF:

0.0415

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0374

Gnomad OTH

AF:

0.0321

GnomAD2 exomes

AF:

0.0346

AC:

8698

AN:

251228

AF XY:

0.0385

show subpopulations

Gnomad AFR exome

AF:

0.00678

Gnomad AMR exome

AF:

0.0157

Gnomad ASJ exome

AF:

0.0219

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0475

Gnomad NFE exome

AF:

0.0389

Gnomad OTH exome

AF:

0.0424

GnomAD4 exome

AF:

0.0388

AC:

56481

AN:

1454650

Hom.:

1293

Cov.:

AF XY:

0.0400

AC XY:

28950

AN XY:

724138

show subpopulations

African (AFR)

AF:

0.00738

AC:

246

AN:

33334

American (AMR)

AF:

0.0163

AC:

728

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

572

AN:

26104

East Asian (EAS)

AF:

0.000176

AC:

AN:

39674

South Asian (SAS)

AF:

0.0705

AC:

6065

AN:

86078

European-Finnish (FIN)

AF:

0.0474

AC:

2534

AN:

53408

Middle Eastern (MID)

AF:

0.0738

AC:

425

AN:

5760

European-Non Finnish (NFE)

AF:

0.0396

AC:

43796

AN:

1105412

Other (OTH)

AF:

0.0350

AC:

2108

AN:

60162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2696

5392

8089

10785

13481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1654

3308

4962

6616

8270

<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:

0.0269

AC:

4098

AN:

152220

Hom.:

Cov.:

AF XY:

0.0276

AC XY:

2058

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00908

AC:

377

AN:

41538

American (AMR)

AF:

0.0178

AC:

272

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.0632

AC:

305

AN:

4824

European-Finnish (FIN)

AF:

0.0415

AC:

439

AN:

10588

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0374

AC:

2545

AN:

68004

Other (OTH)

AF:

0.0303

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

198

396

595

793

991

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0305

Hom.:

Bravo

AF:

0.0235

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0374

EpiControl

AF:

0.0389

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 09, 2025

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

970+7A>G in intron 4 of HPS3: This variant is not expected to have clinical sign ificance because it is not located within the conserved splice consensus sequenc e. It has been identified in 3.6% (309/8600) of European American chromosomes fr om a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu/EVS; dbSNP rs114029765). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome 3

Benign:3

Dec 16, 2016

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.79

(source)

DANN

Benign

0.38

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000086

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: 31

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