chr3-149141387-A-G

Position:

chr3-149141387-A-G

Variant summary

Our verdict is Benign. Variant got -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:8

Conservation

PhyloP100: -2.35

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 178776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-149141387-A-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
HPS3	NM_032383.5 linkuse as main transcript	c.970+7A>G		splice_region_variant, intron_variant		ENST00000296051.7

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
HPS3	ENST00000296051.7 linkuse as main transcript	c.970+7A>G	splice_region_variant, intron_variant	1	NM_032383.5	P1	Q969F9-1
HPS3	ENST00000460120.5 linkuse as main transcript	c.475+7A>G	splice_region_variant, intron_variant	2
HPS3	ENST00000462030.5 linkuse as main transcript	n.1569+7A>G	splice_region_variant, intron_variant, non_coding_transcript_variant	2
HPS3	ENST00000486530.1 linkuse as main transcript	n.1003+7A>G	splice_region_variant, intron_variant, non_coding_transcript_variant	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

GnomAD3 exomes

AF:

0.0346

AC:

8698

AN:

251228

Hom.:

223

AF XY:

0.0385

AC XY:

5226

AN XY:

135790

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 SAS exome

AF:

0.0690

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

Gnomad4 AFR exome

AF:

0.00738

Gnomad4 AMR exome

AF:

0.0163

Gnomad4 ASJ exome

AF:

0.0219

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0705

Gnomad4 FIN exome

AF:

0.0474

Gnomad4 NFE exome

AF:

0.0396

Gnomad4 OTH exome

AF:

0.0350

GnomAD4 genome

AF:

0.0269

AC:

4098

AN:

152220

Hom.:

Cov.:

AF XY:

0.0276

AC XY:

2058

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00908

Gnomad4 AMR

AF:

0.0178

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0632

Gnomad4 FIN

AF:

0.0415

Gnomad4 NFE

AF:

0.0374

Gnomad4 OTH

AF:

0.0303

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 16, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hermansky-Pudlak syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.79

DANN

Benign

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over