dbSNP rs17853184: HPS5:p.Glu1016Lys (chr11-18283807-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_181507.2(HPS5):c.3046G>A(p.Glu1016Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,607,104 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 8 hom. )

Consequence

HPS5
NM_181507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 1.82

Publications

6 publications found

Variant links:

Genes affected

HPS5 (HGNC:17022): (HPS5 biogenesis of lysosomal organelles complex 2 subunit 2) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 6 protein and may interact with the cytoplasmic domain of integrin, alpha-3. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 5. Multiple transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

HPS5 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
Hermansky-Pudlak syndrome without pulmonary fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HPS5 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_181507.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011577249).

BP6

Variant 11-18283807-C-T is Benign according to our data. Variant chr11-18283807-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 303870.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00139 (212/152292) while in subpopulation AMR AF = 0.00294 (45/15286). AF 95% confidence interval is 0.00226. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS5	NM_181507.2	MANE Select	c.3046G>A	p.Glu1016Lys	missense	Exon 21 of 23	NP_852608.1	Q9UPZ3-1
HPS5	NM_001440902.1		c.3046G>A	p.Glu1016Lys	missense	Exon 21 of 24	NP_001427831.1
HPS5	NM_001440903.1		c.3046G>A	p.Glu1016Lys	missense	Exon 21 of 24	NP_001427832.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPS5	ENST00000349215.8	TSL:1 MANE Select	c.3046G>A	p.Glu1016Lys	missense	Exon 21 of 23	ENSP00000265967.5	Q9UPZ3-1
HPS5	ENST00000396253.7	TSL:1	c.2704G>A	p.Glu902Lys	missense	Exon 20 of 22	ENSP00000379552.3	Q9UPZ3-2
HPS5	ENST00000438420.6	TSL:1	c.2704G>A	p.Glu902Lys	missense	Exon 20 of 22	ENSP00000399590.2	Q9UPZ3-2

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

212

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00134

AC:

337

AN:

251090

AF XY:

0.00141

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000469

Gnomad NFE exome

AF:

0.00237

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00165

AC:

2399

AN:

1454812

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1156

AN XY:

724276

show subpopulations

African (AFR)

AF:

0.000300

AC:

AN:

33332

American (AMR)

AF:

0.000984

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000192

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.000534

AC:

AN:

86106

European-Finnish (FIN)

AF:

0.00102

AC:

AN:

53046

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00194

AC:

2140

AN:

1105946

Other (OTH)

AF:

0.00145

AC:

AN:

60176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

103

207

310

414

517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.00139

AC:

212

AN:

152292

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41564

American (AMR)

AF:

0.00294

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000755

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00215

AC:

146

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00176

Hom.:

Bravo

AF:

0.00181

EpiCase

AF:

0.00289

EpiControl

AF:

0.00172

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hermansky-Pudlak syndrome 5 (3)

not provided (2)

HPS5-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

-0.037

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.011

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

PhyloP100

1.8

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.89

REVEL

Benign

0.019

Sift

Benign

0.033

Sift4G

Benign

0.061

Varity_R

0.13

gMVP

0.41

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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