rs61884288

chr11-18281986-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.18

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]

ACMG classification

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 GnomAd at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2	c.3293C>T	p.Thr1098Ile	missense_variant	22/23	ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8	c.3293C>T	p.Thr1098Ile	missense_variant	22/23	1	NM_181507.2	P1

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3591 AN: 152124 Hom.: 57 Cov.: 32

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

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.: 33 AF XY: 0.0334 AC XY: 24264 AN XY: 727210

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.: 57 Cov.: 32 AF XY: 0.0212 AC XY: 1579 AN XY: 74446

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: 34

ESP6500EA AF: 0.0373 AC: 320

ExAC AF: 0.0236 AC: 2868

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0357

EpiControl AF: 0.0369

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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

Hermansky-Pudlak syndrome 5 Benign:2

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 -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	-0.061
Eigen_PC	Benign	0.054
FATHMM_MKL	Benign	0.72	D
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.021	A;A;A;A
PrimateAI	Uncertain	0.48	T
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	T
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

Other links and lift over

dbSNP: rs61884288; hg19: chr11-18303533; COSMIC: COSV61687117; COSMIC: COSV61687117;