11-18281986-G-A

Position:

chr11-18281986-G-A

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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

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=0.0136913955).

BP6

Variant 11-18281986-G-A is Benign according to our data. Variant chr11-18281986-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-18281986-G-A is described in UniProt as null. Variant chr11-18281986-G-A is described in Lovd as [Benign]. Variant chr11-18281986-G-A is described in Lovd as [Pathogenic]. Variant chr11-18281986-G-A is described in Lovd as [Likely_benign].

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

BS2

High Homozygotes in GnomAd4 at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS5	NM_181507.2 linkuse as main transcript	c.3293C>T	p.Thr1098Ile	missense_variant	22/23	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.3293C>T	p.Thr1098Ile	missense_variant	22/23	1	NM_181507.2	ENSP00000265967	P1	Q9UPZ3-1

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

GnomAD3 exomes

AF:

0.0237

AC:

5954

AN:

251468

Hom.:

105

AF XY:

0.0235

AC XY:

3196

AN XY:

135912

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 SAS exome

AF:

0.00699

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

Gnomad4 AFR exome

AF:

0.00490

Gnomad4 AMR exome

AF:

0.0152

Gnomad4 ASJ exome

AF:

0.0408

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00741

Gnomad4 FIN exome

AF:

0.0176

Gnomad4 NFE exome

AF:

0.0401

Gnomad4 OTH exome

AF:

0.0286

GnomAD4 genome

AF:

0.0236

AC:

3590

AN:

152242

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1579

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00705

Gnomad4 AMR

AF:

0.0180

Gnomad4 ASJ

AF:

0.0421

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00436

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.0387

Gnomad4 OTH

AF:

0.0308

Alfa

AF:

0.0355

Hom.:

174

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 12, 2014	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). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2017	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2019	This variant is associated with the following publications: (PMID: 15296495, 16420244, 17365864, 28640947, 29090612, 27884173, 22995991, 28296950, 25333069, 20981092) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hermansky-Pudlak syndrome 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	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

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;.;.

MutationTaster

Benign

0.021

A;A;A;A

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

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