rs17853184

Positions:

• chr11-18283807-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_181507.2(HPS5):​c.3046G>A​(p.Glu1016Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,607,104 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (8 hom.)
• Consequence: HPS5 NM_181507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.82

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011577249).
• BP6: Variant 11-18283807-C-T is Benign according to our data. Variant chr11-18283807-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 303870.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr11-18283807-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00139 (212/152292) while in subpopulation AMR AF= 0.00294 (45/15286). AF 95% confidence interval is 0.00226. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS5	NM_181507.2	c.3046G>A	p.Glu1016Lys	missense_variant	21/23	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.3046G>A	p.Glu1016Lys	missense_variant	21/23	1	NM_181507.2	ENSP00000265967.5

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00134 AC: 337 AN: 251090 Hom.: 1 AF XY: 0.00141 AC XY: 192 AN XY: 135752

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.000469

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00165 AC: 2399 AN: 1454812 Hom.: 8 Cov.: 29 AF XY: 0.00160 AC XY: 1156 AN XY: 724276

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000534

Gnomad4 FIN exome AF: 0.00102

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00145

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74460

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00181 Hom.: 1

Bravo AF: 0.00181

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00245 AC: 21

ExAC AF: 0.00154 AC: 187

EpiCase AF: 0.00289

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hermansky-Pudlak syndrome 5 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 03, 2018

The p.Glu1016Lys variant in HPS5 is classified as likely benign because it has b een identified in 0.23 % (290/126656) of European chromosomes by the Genome Aggr egation Database (gnomAD, http://gnomad.broadinstitute.org) and computational pr ediction tools and conservation analysis suggest that the p.Glu1016Lys variant m ay not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

HPS5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2023

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	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T;.;.
Eigen	Benign	-0.037
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	.;L;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.89	N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.033	D;D;D;D
Sift4G	Benign	0.061	T;T;T;T
Polyphen		0.20	.;B;.;.
Vest4		0.28
MVP		0.63
MPC		0.079
ClinPred		0.012	T
GERP RS		5.1
Varity_R		0.13
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17853184; hg19: chr11-18305354; COSMIC: COSV100752392; COSMIC: COSV100752392;