rs61884288

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.3293C>T(p.Thr1098Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0331 in 1,614,064 control chromosomes in the GnomAD database, including 1,023 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 57 hom., cov: 32)

Exomes 𝑓: 0.034 ( 966 hom. )

Consequence

HPS5
NM_181507.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.18

Publications

16 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=0.0136913955).

BP6

Variant 11-18281986-G-A is Benign according to our data. Variant chr11-18281986-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21821.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 = 0.0236 (3590/152242) while in subpopulation NFE AF = 0.0387 (2634/68022). AF 95% confidence interval is 0.0375. There are 57 homozygotes in GnomAd4. There are 1579 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2 link	c.3293C>T	p.Thr1098Ile	missense_variant	Exon 22 of 23	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8 link	c.3293C>T	p.Thr1098Ile	missense_variant	Exon 22 of 23	1	NM_181507.2	ENSP00000265967.5

Frequencies

GnomAD3 genomes

AF:

0.0236

AC:

3591

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00708

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0180

Gnomad ASJ

AF:

0.0421

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0387

Gnomad OTH

AF:

0.0311

GnomAD2 exomes

AF:

0.0237

AC:

5954

AN:

251468

AF XY:

0.0235

show subpopulations

Gnomad AFR exome

AF:

0.00671

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.0420

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.0372

Gnomad OTH exome

AF:

0.0230

GnomAD4 exome

AF:

0.0341

AC:

49878

AN:

1461822

Hom.:

966

Cov.:

AF XY:

0.0334

AC XY:

24264

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00490

AC:

164

AN:

33480

American (AMR)

AF:

0.0152

AC:

680

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0408

AC:

1066

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00741

AC:

639

AN:

86256

European-Finnish (FIN)

AF:

0.0176

AC:

939

AN:

53420

Middle Eastern (MID)

AF:

0.0161

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0401

AC:

44567

AN:

1111942

Other (OTH)

AF:

0.0286

AC:

1729

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

2758

5515

8273

11030

13788

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1648

3296

4944

6592

8240

<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:

0.0236

AC:

3590

AN:

152242

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1579

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00705

AC:

293

AN:

41534

American (AMR)

AF:

0.0180

AC:

275

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0421

AC:

146

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00436

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0140

AC:

149

AN:

10608

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0387

AC:

2634

AN:

68022

Other (OTH)

AF:

0.0308

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

177

355

532

710

887

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0333

Hom.:

341

Bravo

AF:

0.0229

TwinsUK

AF:

0.0391

AC:

145

ALSPAC

AF:

0.0439

AC:

169

ESP6500AA

AF:

0.00773

AC:

ESP6500EA

AF:

0.0373

AC:

320

ExAC

AF:

0.0236

AC:

2868

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0357

EpiControl

AF:

0.0369

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 24, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Thr1098Ile in exon 22 of HPS5: This variant is not expected to have clinical s ignificance because it has been identified in 3.7% (320/8586) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs61884288). -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 31, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15296495, 16420244, 17365864, 28640947, 29090612, 27884173, 22995991, 28296950, 25333069, 20981092) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hermansky-Pudlak syndrome 5

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

European Non-Finnish population allele frequency is 3.63% (rs61884288, 436/10370 alleles, 6 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.0, this variant is classified as BENIGN. Following criteria are met: BA1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;T;.;.

Eigen

Benign

-0.061

Eigen_PC

Benign

0.054

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.83

.;T;T;T

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L;.;.

PhyloP100

4.2

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.19

N;N;N;N

REVEL

Benign

0.045

Sift

Benign

0.29

T;T;T;T

Sift4G

Benign

0.14

T;T;T;D

Polyphen

0.46

.;P;.;.

Vest4

0.49

MPC

0.057

ClinPred

0.012

GERP RS

3.9

Varity_R

0.022

gMVP

0.21

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over