Genetic Variant HPS3:c.2589+1G>T (chr3-149163950-G-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_ModeratePS3PM2PP5_Very_Strong

The NM_032383.5(HPS3):c.2589+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000241 in 1,409,338 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 (★★). ClinVar reports functional evidence for this variant: "SCV001409211: Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (PMID:11590544).".

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 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:4

Conservation

PhyloP100: 7.63

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 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Ambry Genetics, Orphanet
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: Pathogenic. The variant received 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035820894 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.6, offset of 50, new splice context is: agtGTaaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001409211: Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (PMID: 11590544).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-149163950-G-T is Pathogenic according to our data. Variant chr3-149163950-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 962603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032383.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HPS3	NM_032383.5	MANE Select	c.2589+1G>T	splice_donor intron	N/A	NP_115759.2
HPS3	NM_001308258.2		c.2094+1G>T	splice_donor intron	N/A	NP_001295187.1	G5E9V4
CP	NR_046371.2		n.2948-1075C>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HPS3	ENST00000296051.7	TSL:1 MANE Select	c.2589+1G>T	splice_donor intron	N/A	ENSP00000296051.2	Q969F9-1
HPS3	ENST00000870872.1		c.2574+1G>T	splice_donor intron	N/A	ENSP00000540931.1
HPS3	ENST00000870871.1		c.2589+1G>T	splice_donor intron	N/A	ENSP00000540930.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

247318

AF XY:

0.00000747

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1257188

Hom.:

Cov.:

AF XY:

0.0000189

AC XY:

AN XY:

635984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30158

American (AMR)

AF:

0.00

AC:

AN:

44256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24946

East Asian (EAS)

AF:

0.00

AC:

AN:

38526

South Asian (SAS)

AF:

0.00

AC:

AN:

81866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5004

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

925952

Other (OTH)

AF:

0.0000187

AC:

AN:

53596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.00

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hermansky-Pudlak syndrome 3 (2)

Hermansky-Pudlak syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.6

GERP RS

6.0

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.52

Position offset: -2

DS_DL_spliceai

1.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over