rs17853184

Variant names:

• chr11-18283807-C-T
• rs17853184
• NM_181507.2:c.3046G>A

Variant summary

Our verdict is Benign. The variant received -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. 16/22 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
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Hermansky-Pudlak syndrome without pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 303870.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	NM_181507.2	MANE Select	c.3046G>A	p.Glu1016Lys	missense	Exon 21 of 23	NP_852608.1
	HPS5	NM_001440902.1		c.3046G>A	p.Glu1016Lys	missense	Exon 21 of 24	NP_001427831.1
	HPS5	NM_001440903.1		c.3046G>A	p.Glu1016Lys	missense	Exon 21 of 24	NP_001427832.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	ENST00000349215.8	TSL:1 MANE Select	c.3046G>A	p.Glu1016Lys	missense	Exon 21 of 23	ENSP00000265967.5
	HPS5	ENST00000396253.7	TSL:1	c.2704G>A	p.Glu902Lys	missense	Exon 20 of 22	ENSP00000379552.3
	HPS5	ENST00000438420.6	TSL:1	c.2704G>A	p.Glu902Lys	missense	Exon 20 of 22	ENSP00000399590.2

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

GnomAD2 exomes AF: 0.00134 AC: 337 AN: 251090 AF XY: 0.00141

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 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

African (AFR) AF: 0.000300 AC: 10 AN: 33332

American (AMR) AF: 0.000984 AC: 44 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.000534 AC: 46 AN: 86106

European-Finnish (FIN) AF: 0.00102 AC: 54 AN: 53046

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5762

European-Non Finnish (NFE) AF: 0.00194 AC: 2140 AN: 1105946

Other (OTH) AF: 0.00145 AC: 87 AN: 60176

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

African (AFR) AF: 0.000241 AC: 10 AN: 41564

American (AMR) AF: 0.00294 AC: 45 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00176 Hom.: 3

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

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not specified Benign:1

Jul 03, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HPS5-related disorder Benign:1

Apr 18, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

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
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.8
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.019
Sift	Benign	0.033	D
Sift4G	Benign	0.061	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs17853184; hg19: chr11-18305354; COSMIC: COSV100752392; COSMIC: COSV100752392;