rs143784823

Positions:

chr11-18296807-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000349215.8(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. 14/20 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
ENST00000349215.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.517

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=0.0039352775).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS5	NM_181507.2 linkuse as main transcript	c.1501G>A	p.Gly501Arg	missense_variant	12/23	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8 linkuse as main transcript	c.1501G>A	p.Gly501Arg	missense_variant	12/23	1	NM_181507.2	ENSP00000265967	P1	Q9UPZ3-1
HPS5	ENST00000396253.7 linkuse as main transcript	c.1159G>A	p.Gly387Arg	missense_variant	11/22	1		ENSP00000379552		Q9UPZ3-2
HPS5	ENST00000438420.6 linkuse as main transcript	c.1159G>A	p.Gly387Arg	missense_variant	11/22	1		ENSP00000399590		Q9UPZ3-2
HPS5	ENST00000531848.1 linkuse as main transcript	c.1159G>A	p.Gly387Arg	missense_variant	11/11	5		ENSP00000431758

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

GnomAD3 exomes

AF:

0.00443

AC:

1113

AN:

251342

Hom.:

AF XY:

0.00448

AC XY:

608

AN XY:

135838

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 SAS exome

AF:

0.00114

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

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00184

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00110

Gnomad4 FIN exome

AF:

0.0202

Gnomad4 NFE exome

AF:

0.00306

Gnomad4 OTH exome

AF:

0.00247

GnomAD4 genome

AF:

0.00399

AC:

607

AN:

152236

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

336

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.0208

Gnomad4 NFE

AF:

0.00518

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00398

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

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	HPS5: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -

Hermansky-Pudlak syndrome 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2019

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

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;.;.

MutationTaster

Benign

1.0

N;N;N;N

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

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

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