NM_181507.2:c.1249C>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_181507.2(HPS5):c.1249C>A(p.Leu417Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,613,356 control chromosomes in the GnomAD database, including 10,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1535 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9183 hom. )

Consequence

HPS5
NM_181507.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.25

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015209019).

BP6

Variant 11-18297633-G-T is Benign according to our data. Variant chr11-18297633-G-T is described in ClinVar as [Benign]. Clinvar id is 163677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2 link	c.1249C>A	p.Leu417Met	missense_variant	Exon 11 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.1249C>A	p.Leu417Met	missense_variant	Exon 11 of 23	1	NM_181507.2	ENSP00000265967.5	Q9UPZ3-1
HPS5	ENST00000396253.7 link	c.907C>A	p.Leu303Met	missense_variant	Exon 10 of 22	1		ENSP00000379552.3	Q9UPZ3-2
HPS5	ENST00000438420.6 link	c.907C>A	p.Leu303Met	missense_variant	Exon 10 of 22	1		ENSP00000399590.2	Q9UPZ3-2
HPS5	ENST00000531848.1 link	c.907C>A	p.Leu303Met	missense_variant	Exon 10 of 11	5		ENSP00000431758.1	G3V159

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

20876

AN:

152092

Hom.:

1532

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.154

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.130

Gnomad FIN

AF:

0.175

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.146

GnomAD3 exomes

AF:

0.136

AC:

34133

AN:

251352

Hom.:

2732

AF XY:

0.131

AC XY:

17765

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.212

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.119

Gnomad SAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.161

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

AF:

0.106

AC:

155104

AN:

1461144

Hom.:

9183

Cov.:

AF XY:

0.106

AC XY:

77401

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.186

Gnomad4 AMR exome

AF:

0.204

Gnomad4 ASJ exome

AF:

0.120

Gnomad4 EAS exome

AF:

0.153

Gnomad4 SAS exome

AF:

0.127

Gnomad4 FIN exome

AF:

0.159

Gnomad4 NFE exome

AF:

0.0931

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

AF:

0.137

AC:

20887

AN:

152212

Hom.:

1535

Cov.:

AF XY:

0.140

AC XY:

10447

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.184

Gnomad4 AMR

AF:

0.154

Gnomad4 ASJ

AF:

0.123

Gnomad4 EAS

AF:

0.120

Gnomad4 SAS

AF:

0.129

Gnomad4 FIN

AF:

0.175

Gnomad4 NFE

AF:

0.102

Gnomad4 OTH

AF:

0.145

Alfa

AF:

0.111

Hom.:

2518

Bravo

AF:

0.138

TwinsUK

AF:

0.0944

AC:

350

ALSPAC

AF:

0.0825

AC:

318

ESP6500AA

AF:

0.189

AC:

833

ESP6500EA

AF:

0.0988

AC:

848

ExAC

AF:

0.135

AC:

16378

Asia WGS

AF:

0.140

AC:

488

AN:

3478

EpiCase

AF:

0.110

EpiControl

AF:

0.117

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

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

Leu417Met in exon 11 of HPS5: This variant is not expected to have clinical sign ificance because it has been identified in 18.9% (833/4398) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs7128017). -

Hermansky-Pudlak syndrome 5

Benign:1

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;T;.;.

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

.;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

.;M;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.98

N;N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.027

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.32

MPC

0.33

ClinPred

0.026

GERP RS

2.3

Varity_R

0.28

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over