NM_181507.2:c.1501G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_181507.2(HPS5):c.1501G>A(p.Gly501Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,613,972 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G501G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0040 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 31 hom. )

Consequence

HPS5
NM_181507.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.517

Publications

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

HPS5 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 (MetaRNN=0.0039352775).

BP6

Variant 11-18296807-C-T is Benign according to our data. Variant chr11-18296807-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 303888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00399 (607/152236) while in subpopulation NFE AF = 0.00518 (352/68010). AF 95% confidence interval is 0.00473. There are 5 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2 link	c.1501G>A	p.Gly501Arg	missense_variant	Exon 12 of 23	ENST00000349215.8	NP_852608.1	Q9UPZ3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HPS5	ENST00000349215.8 link	c.1501G>A	p.Gly501Arg	missense_variant	Exon 12 of 23	1	NM_181507.2	ENSP00000265967.5	Q9UPZ3-1
HPS5	ENST00000396253.7 link	c.1159G>A	p.Gly387Arg	missense_variant	Exon 11 of 22	1		ENSP00000379552.3	Q9UPZ3-2
HPS5	ENST00000438420.6 link	c.1159G>A	p.Gly387Arg	missense_variant	Exon 11 of 22	1		ENSP00000399590.2	Q9UPZ3-2
HPS5	ENST00000531848.1 link	c.1159G>A	p.Gly387Arg	missense_variant	Exon 11 of 11	5		ENSP00000431758.1	G3V159

Frequencies

GnomAD3 genomes

AF:

0.00398

AC:

606

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.0208

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00518

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00443

AC:

1113

AN:

251342

AF XY:

0.00448

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.00498

Gnomad OTH exome

AF:

0.00407

GnomAD4 exome

AF:

0.00329

AC:

4811

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

2539

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.000559

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00110

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0202

AC:

1081

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00306

AC:

3399

AN:

1111874

Other (OTH)

AF:

0.00247

AC:

149

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

278

556

834

1112

1390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.00399

AC:

607

AN:

152236

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

336

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41546

American (AMR)

AF:

0.000196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.000623

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0208

AC:

220

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00518

AC:

352

AN:

68010

Other (OTH)

AF:

0.00237

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

123

154

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:

0.00397

Hom.:

Bravo

AF:

0.00206

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00373

AC:

ExAC

AF:

0.00441

AC:

535

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00278

EpiControl

AF:

0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HPS5: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Nov 20, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gly501Arg in exon 12 of HPS5: This variant is not expected to have clinical sign ificance because it has been identified in 4.3% (8/186) of Finnish chromosomes f rom a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/ projects/SNP; dbSNP rs143784823). -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome 5

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

HPS5-related disorder

Benign:1

Aug 01, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.097

.;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.58

.;T;T;T

MetaRNN

Benign

0.0039

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

.;L;.;.

PhyloP100

0.52

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.42

N;N;N;N

REVEL

Benign

0.028

Sift

Benign

0.66

T;T;T;T

Sift4G

Benign

0.68

T;T;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.16

MutPred

0.14

.;Gain of phosphorylation at S499 (P = 0.1251);.;.;

MVP

0.34

MPC

0.060

ClinPred

0.00056

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.019

gMVP

0.24

Mutation Taster

=96/4

polymorphism

(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