3-149167290-C-T

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.2796+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,428,630 control chromosomes in the GnomAD database, including 137,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 17050 hom., cov: 33)

Exomes 𝑓: 0.43 ( 120443 hom. )

Consequence

HPS3
NM_032383.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.213

Publications

11 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 links:

CP (HGNC:2295): (ceruloplasmin) The protein encoded by this gene is a metalloprotein that binds most of the copper in plasma and is involved in the peroxidation of Fe(II)transferrin to Fe(III) transferrin. Mutations in this gene cause aceruloplasminemia, which results in iron accumulation and tissue damage, and is associated with diabetes and neurologic abnormalities. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Feb 2012]

CP Gene-Disease associations (from GenCC):

aceruloplasminemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
disorder of iron metabolism and transport
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CP 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=-0.89).

BP6

Variant 3-149167290-C-T is Benign according to our data. Variant chr3-149167290-C-T is described in ClinVar as Benign. ClinVar VariationId is 262024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS3	NM_032383.5 link	c.2796+50C>T		intron_variant	Intron 15 of 16	ENST00000296051.7	NP_115759.2	Q969F9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS3	ENST00000296051.7 link	c.2796+50C>T		intron_variant	Intron 15 of 16	1	NM_032383.5	ENSP00000296051.2		Q969F9-1

Frequencies

GnomAD3 genomes

AF:

0.464

AC:

70462

AN:

151914

Hom.:

17028

Cov.:

show subpopulations

Gnomad AFR

AF:

0.597

Gnomad AMI

AF:

0.370

Gnomad AMR

AF:

0.340

Gnomad ASJ

AF:

0.305

Gnomad EAS

AF:

0.389

Gnomad SAS

AF:

0.577

Gnomad FIN

AF:

0.441

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.423

Gnomad OTH

AF:

0.416

GnomAD2 exomes

AF:

0.427

AC:

74918

AN:

175478

AF XY:

0.440

show subpopulations

Gnomad AFR exome

AF:

0.605

Gnomad AMR exome

AF:

0.282

Gnomad ASJ exome

AF:

0.320

Gnomad EAS exome

AF:

0.379

Gnomad FIN exome

AF:

0.433

Gnomad NFE exome

AF:

0.422

Gnomad OTH exome

AF:

0.391

GnomAD4 exome

AF:

0.430

AC:

548806

AN:

1276598

Hom.:

120443

Cov.:

AF XY:

0.435

AC XY:

277929

AN XY:

638964

show subpopulations

African (AFR)

AF:

0.609

AC:

17842

AN:

29320

American (AMR)

AF:

0.287

AC:

10694

AN:

37230

Ashkenazi Jewish (ASJ)

AF:

0.322

AC:

7889

AN:

24526

East Asian (EAS)

AF:

0.367

AC:

13240

AN:

36120

South Asian (SAS)

AF:

0.576

AC:

45236

AN:

78482

European-Finnish (FIN)

AF:

0.432

AC:

20844

AN:

48212

Middle Eastern (MID)

AF:

0.353

AC:

1452

AN:

4108

European-Non Finnish (NFE)

AF:

0.423

AC:

408485

AN:

964588

Other (OTH)

AF:

0.428

AC:

23124

AN:

54012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

15754

31508

47261

63015

78769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12092

24184

36276

48368

60460

<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:

0.464

AC:

70531

AN:

152032

Hom.:

17050

Cov.:

AF XY:

0.464

AC XY:

34474

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.597

AC:

24761

AN:

41444

American (AMR)

AF:

0.339

AC:

5175

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

1059

AN:

3472

East Asian (EAS)

AF:

0.389

AC:

2009

AN:

5166

South Asian (SAS)

AF:

0.577

AC:

2780

AN:

4818

European-Finnish (FIN)

AF:

0.441

AC:

4670

AN:

10578

Middle Eastern (MID)

AF:

0.367

AC:

108

AN:

294

European-Non Finnish (NFE)

AF:

0.423

AC:

28754

AN:

67980

Other (OTH)

AF:

0.417

AC:

878

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1908

3816

5723

7631

9539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

642

1284

1926

2568

3210

<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:

0.432

Hom.:

35686

Bravo

AF:

0.455

Asia WGS

AF:

0.480

AC:

1670

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome 3

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.3

(source)

DANN

Benign

0.36

PhyloP100

0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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