rs149229493

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The ENST00000396253.7(HPS5):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00412 in 1,612,654 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 21 hom. )

Consequence

HPS5
ENST00000396253.7 start_lost

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: 3.84

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 -8 ACMG points.

PVS1

Start lost variant, no new inframe start found.

BP6

Variant 11-18310873-C-T is Benign according to our data. Variant chr11-18310873-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 197894.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 = 0.003 (454/151088) while in subpopulation NFE AF= 0.00489 (331/67646). AF 95% confidence interval is 0.00446. There are 1 homozygotes in gnomad4. There are 217 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2 linkuse as main transcript	c.345G>A	p.Met115Ile	missense_variant	5/23	ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000396253.7 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	4/22	1			Q9UPZ3-2
HPS5	ENST00000438420.6 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	4/22	1			Q9UPZ3-2
HPS5	ENST00000349215.8 linkuse as main transcript	c.345G>A	p.Met115Ile	missense_variant	5/23	1	NM_181507.2	P1	Q9UPZ3-1
HPS5	ENST00000531848.1 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	4/11	5

Frequencies

GnomAD3 genomes

AF:

0.00301

AC:

454

AN:

150966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00191

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00190

Gnomad FIN

AF:

0.00294

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00489

Gnomad OTH

AF:

0.00485

GnomAD3 exomes

AF:

0.00285

AC:

715

AN:

251206

Hom.:

AF XY:

0.00277

AC XY:

376

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00157

Gnomad FIN exome

AF:

0.00287

Gnomad NFE exome

AF:

0.00471

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00424

AC:

6197

AN:

1461566

Hom.:

Cov.:

AF XY:

0.00417

AC XY:

3032

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00134

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00168

Gnomad4 FIN exome

AF:

0.00283

Gnomad4 NFE exome

AF:

0.00508

Gnomad4 OTH exome

AF:

0.00277

GnomAD4 genome

AF:

0.00300

AC:

454

AN:

151088

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

217

AN XY:

73856

show subpopulations

Gnomad4 AFR

AF:

0.00104

Gnomad4 AMR

AF:

0.00191

Gnomad4 ASJ

AF:

0.000290

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00190

Gnomad4 FIN

AF:

0.00294

Gnomad4 NFE

AF:

0.00489

Gnomad4 OTH

AF:

0.00480

Alfa

AF:

0.00428

Hom.:

Bravo

AF:

0.00298

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00396

AC:

ExAC

AF:

0.00281

AC:

341

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00414

EpiControl

AF:

0.00415

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	HPS5: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2015	p.Met115Ile in exon 5 of HPS5: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1492 29493). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2015	- -

Hermansky-Pudlak syndrome 5

Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of autosomal recessive Hermansky-Pudlak syndrome 5 (MIM#614074). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Thrombocytopenia;C1458140:Abnormal bleeding

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HPS5-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2020

This variant is classified as likely 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

0.083

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Benign

0.88

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.62

FATHMM_MKL

Uncertain

0.79

M_CAP

Benign

0.0051

MetaRNN

Benign

0.0092

T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Benign

0.42

PROVEAN

Benign

0.90

N;N;N;N

REVEL

Benign

0.057

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.24

MutPred

0.31

.;Gain of methylation at K111 (P = 0.1407);.;.;

MVP

0.35

MPC

0.056

ClinPred

0.0087

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.032

gMVP

0.081

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