Genetic Variant HPS3:c.217+346C>G (chr3-149130286-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_032383.5(HPS3):c.217+346C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 367,022 control chromosomes in the GnomAD database, including 1,625 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.077 ( 556 hom., cov: 32)

Exomes 𝑓: 0.087 ( 1069 hom. )

Consequence

HPS3
NM_032383.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.301

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS3	NM_032383.5 link	c.217+346C>G		intron_variant	Intron 1 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.217+346C>G		intron_variant	Intron 1 of 16	1	NM_032383.5	ENSP00000296051.2		Q969F9-1

Frequencies

GnomAD3 genomes

AF:

0.0769

AC:

11689

AN:

152032

Hom.:

554

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0467

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.0741

Gnomad ASJ

AF:

0.0871

Gnomad EAS

AF:

0.00810

Gnomad SAS

AF:

0.145

Gnomad FIN

AF:

0.0352

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0818

GnomAD4 exome

AF:

0.0870

AC:

18694

AN:

214872

Hom.:

1069

Cov.:

AF XY:

0.0901

AC XY:

10103

AN XY:

112166

show subpopulations

African (AFR)

AF:

0.0443

AC:

276

AN:

6228

American (AMR)

AF:

0.0633

AC:

515

AN:

8134

Ashkenazi Jewish (ASJ)

AF:

0.0831

AC:

562

AN:

6764

East Asian (EAS)

AF:

0.00621

AC:

AN:

12724

South Asian (SAS)

AF:

0.123

AC:

3002

AN:

24458

European-Finnish (FIN)

AF:

0.0397

AC:

453

AN:

11418

Middle Eastern (MID)

AF:

0.0818

AC:

AN:

966

European-Non Finnish (NFE)

AF:

0.0965

AC:

12670

AN:

131336

Other (OTH)

AF:

0.0824

AC:

1058

AN:

12844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

814

1628

2443

3257

4071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.0769

AC:

11695

AN:

152150

Hom.:

556

Cov.:

AF XY:

0.0736

AC XY:

5476

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0467

AC:

1937

AN:

41508

American (AMR)

AF:

0.0740

AC:

1131

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0871

AC:

302

AN:

3468

East Asian (EAS)

AF:

0.00812

AC:

AN:

5174

South Asian (SAS)

AF:

0.145

AC:

698

AN:

4826

European-Finnish (FIN)

AF:

0.0352

AC:

372

AN:

10580

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6942

AN:

68002

Other (OTH)

AF:

0.0862

AC:

182

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

550

1100

1650

2200

2750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<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:

0.0340

Hom.:

Bravo

AF:

0.0751

Asia WGS

AF:

0.0830

AC:

291

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

3.9

(source)

DANN

Benign

0.39

PhyloP100

0.30

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

Computational scores

Splicing

Publications

Other links and lift over