Genetic Variant NM_032383.5:c.2526C>T (chr3-149163886-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_032383.5(HPS3):c.2526C>T(p.His842His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,567,320 control chromosomes in the GnomAD database, including 29,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2511 hom., cov: 32)

Exomes 𝑓: 0.19 ( 27392 hom. )

Consequence

HPS3
NM_032383.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.484

Publications

25 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 3-149163886-C-T is Benign according to our data. Variant chr3-149163886-C-T is described in ClinVar as Benign. ClinVar VariationId is 163669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.484 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS3	NM_032383.5	MANE Select	c.2526C>T	p.His842His	synonymous	Exon 14 of 17	NP_115759.2
HPS3	NM_001308258.2		c.2031C>T	p.His677His	synonymous	Exon 13 of 16	NP_001295187.1	G5E9V4
CP	NR_046371.2		n.2948-1011G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS3	ENST00000296051.7	TSL:1 MANE Select	c.2526C>T	p.His842His	synonymous	Exon 14 of 17	ENSP00000296051.2	Q969F9-1
HPS3	ENST00000870872.1		c.2511C>T	p.His837His	synonymous	Exon 14 of 17	ENSP00000540931.1
HPS3	ENST00000870871.1		c.2526C>T	p.His842His	synonymous	Exon 14 of 17	ENSP00000540930.1

Frequencies

GnomAD3 genomes

AF:

0.160

AC:

24256

AN:

152014

Hom.:

2513

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0437

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.273

Gnomad SAS

AF:

0.215

Gnomad FIN

AF:

0.274

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.206

Gnomad OTH

AF:

0.135

GnomAD2 exomes

AF:

0.186

AC:

46378

AN:

249622

AF XY:

0.190

show subpopulations

Gnomad AFR exome

AF:

0.0395

Gnomad AMR exome

AF:

0.125

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.278

Gnomad FIN exome

AF:

0.255

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.168

GnomAD4 exome

AF:

0.189

AC:

267329

AN:

1415188

Hom.:

27392

Cov.:

AF XY:

0.191

AC XY:

134558

AN XY:

706272

show subpopulations

African (AFR)

AF:

0.0347

AC:

1148

AN:

33116

American (AMR)

AF:

0.127

AC:

5657

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

2736

AN:

25924

East Asian (EAS)

AF:

0.259

AC:

10166

AN:

39252

South Asian (SAS)

AF:

0.202

AC:

17184

AN:

85154

European-Finnish (FIN)

AF:

0.251

AC:

13337

AN:

53120

Middle Eastern (MID)

AF:

0.0697

AC:

393

AN:

5638

European-Non Finnish (NFE)

AF:

0.193

AC:

206217

AN:

1069694

Other (OTH)

AF:

0.179

AC:

10491

AN:

58758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

8989

17977

26966

35954

44943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6804

13608

20412

27216

34020

<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:

0.159

AC:

24258

AN:

152132

Hom.:

2511

Cov.:

AF XY:

0.163

AC XY:

12104

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0436

AC:

1809

AN:

41526

American (AMR)

AF:

0.141

AC:

2159

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

365

AN:

3470

East Asian (EAS)

AF:

0.274

AC:

1420

AN:

5182

South Asian (SAS)

AF:

0.216

AC:

1040

AN:

4824

European-Finnish (FIN)

AF:

0.274

AC:

2890

AN:

10538

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.206

AC:

14026

AN:

67994

Other (OTH)

AF:

0.135

AC:

286

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1029

2058

3088

4117

5146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.170

Hom.:

5893

Bravo

AF:

0.143

Asia WGS

AF:

0.215

AC:

750

AN:

3478

EpiCase

AF:

0.185

EpiControl

AF:

0.183

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hermansky-Pudlak syndrome 3 (2)

not specified (2)

Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.2

(source)

DANN

Benign

0.77

PhyloP100

-0.48

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over