Genetic Variant HPS5:p.Leu274Leu (chr11-18306137-G-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_181507.2(HPS5):c.822C>A(p.Leu274Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 1,597,472 control chromosomes in the GnomAD database, including 410,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 40614 hom., cov: 32)

Exomes 𝑓: 0.71 ( 370185 hom. )

Consequence

HPS5
NM_181507.2 splice_region, synonymous

Scores

Splicing: ADA: 0.00007983

Clinical Significance

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

Conservation

PhyloP100: 1.30

Publications

25 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 11-18306137-G-T is Benign according to our data. Variant chr11-18306137-G-T is described in ClinVar as Benign. ClinVar VariationId is 163678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.3 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

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
HPS5	NM_181507.2	MANE Select	c.822C>A	p.Leu274Leu	splice_region synonymous	Exon 7 of 23	NP_852608.1
HPS5	NM_001440902.1		c.822C>A	p.Leu274Leu	splice_region synonymous	Exon 7 of 24	NP_001427831.1
HPS5	NM_001440903.1		c.822C>A	p.Leu274Leu	splice_region synonymous	Exon 7 of 24	NP_001427832.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HPS5	ENST00000349215.8	TSL:1 MANE Select	c.822C>A	p.Leu274Leu	splice_region synonymous	Exon 7 of 23	ENSP00000265967.5
HPS5	ENST00000396253.7	TSL:1	c.480C>A	p.Leu160Leu	splice_region synonymous	Exon 6 of 22	ENSP00000379552.3
HPS5	ENST00000438420.6	TSL:1	c.480C>A	p.Leu160Leu	splice_region synonymous	Exon 6 of 22	ENSP00000399590.2

Frequencies

GnomAD3 genomes

AF:

0.727

AC:

110426

AN:

151934

Hom.:

40566

Cov.:

show subpopulations

Gnomad AFR

AF:

0.764

Gnomad AMI

AF:

0.763

Gnomad AMR

AF:

0.746

Gnomad ASJ

AF:

0.590

Gnomad EAS

AF:

0.969

Gnomad SAS

AF:

0.750

Gnomad FIN

AF:

0.720

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.689

Gnomad OTH

AF:

0.711

GnomAD2 exomes

AF:

0.732

AC:

183949

AN:

251348

AF XY:

0.723

show subpopulations

Gnomad AFR exome

AF:

0.765

Gnomad AMR exome

AF:

0.812

Gnomad ASJ exome

AF:

0.580

Gnomad EAS exome

AF:

0.976

Gnomad FIN exome

AF:

0.715

Gnomad NFE exome

AF:

0.684

Gnomad OTH exome

AF:

0.682

GnomAD4 exome

AF:

0.713

AC:

1030552

AN:

1445420

Hom.:

370185

Cov.:

AF XY:

0.711

AC XY:

511979

AN XY:

720278

show subpopulations

African (AFR)

AF:

0.760

AC:

25205

AN:

33150

American (AMR)

AF:

0.803

AC:

35889

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.581

AC:

15114

AN:

26030

East Asian (EAS)

AF:

0.962

AC:

38134

AN:

39620

South Asian (SAS)

AF:

0.721

AC:

61938

AN:

85926

European-Finnish (FIN)

AF:

0.713

AC:

38095

AN:

53412

Middle Eastern (MID)

AF:

0.544

AC:

3122

AN:

5744

European-Non Finnish (NFE)

AF:

0.702

AC:

770448

AN:

1097030

Other (OTH)

AF:

0.712

AC:

42607

AN:

59804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

13011

26022

39034

52045

65056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19536

39072

58608

78144

97680

<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:

0.727

AC:

110530

AN:

152052

Hom.:

40614

Cov.:

AF XY:

0.730

AC XY:

54286

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.764

AC:

31696

AN:

41492

American (AMR)

AF:

0.746

AC:

11394

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.590

AC:

2047

AN:

3470

East Asian (EAS)

AF:

0.969

AC:

5019

AN:

5182

South Asian (SAS)

AF:

0.750

AC:

3607

AN:

4808

European-Finnish (FIN)

AF:

0.720

AC:

7598

AN:

10548

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.689

AC:

46797

AN:

67966

Other (OTH)

AF:

0.714

AC:

1508

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1522

3044

4565

6087

7609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<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:

0.698

Hom.:

127952

Bravo

AF:

0.733

Asia WGS

AF:

0.888

AC:

3084

AN:

3478

EpiCase

AF:

0.675

EpiControl

AF:

0.671

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 09, 2025

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Hermansky-Pudlak syndrome 5

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 13, 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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

7.0

(source)

DANN

Benign

0.71

PhyloP100

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000080

dbscSNV1_RF

Benign

0.022

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over