11-18283786-T-C

Variant names:

• chr11-18283786-T-C
• rs2049129
• NM_181507.2:c.3058+9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181507.2(HPS5):​c.3058+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,582,672 control chromosomes in the GnomAD database, including 25,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3241 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21959 hom.)
• Consequence: HPS5 NM_181507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.526
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 11-18283786-T-C is Benign according to our data. Variant chr11-18283786-T-C is described in ClinVar as Benign. ClinVar VariationId is 163676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.3058+9A>G		intron_variant	Intron 21 of 22	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.3058+9A>G		intron_variant	Intron 21 of 22	1	NM_181507.2	ENSP00000265967.5

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29327 AN: 151954 Hom.: 3236 Cov.: 32

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0603

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.176

GnomAD2 exomes AF: 0.147 AC: 36894 AN: 250774 AF XY: 0.145

Gnomad AFR exome AF: 0.285

Gnomad AMR exome AF: 0.0823

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.169 AC: 241073 AN: 1430600 Hom.: 21959 Cov.: 26 AF XY: 0.166 AC XY: 118264 AN XY: 713432

African (AFR) AF: 0.296 AC: 9704 AN: 32824

American (AMR) AF: 0.0873 AC: 3900 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4233 AN: 25940

East Asian (EAS) AF: 0.000835 AC: 33 AN: 39532

South Asian (SAS) AF: 0.0775 AC: 6636 AN: 85670

European-Finnish (FIN) AF: 0.211 AC: 11102 AN: 52696

Middle Eastern (MID) AF: 0.184 AC: 1048 AN: 5692

European-Non Finnish (NFE) AF: 0.180 AC: 194824 AN: 1084134

Other (OTH) AF: 0.161 AC: 9593 AN: 59426

GnomAD4 genome AF: 0.193 AC: 29347 AN: 152072 Hom.: 3241 Cov.: 32 AF XY: 0.189 AC XY: 14039 AN XY: 74340

African (AFR) AF: 0.285 AC: 11814 AN: 41438

American (AMR) AF: 0.124 AC: 1898 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5180

South Asian (SAS) AF: 0.0604 AC: 291 AN: 4818

European-Finnish (FIN) AF: 0.203 AC: 2147 AN: 10582

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12146 AN: 67982

Other (OTH) AF: 0.173 AC: 366 AN: 2110

Alfa AF: 0.177 Hom.: 8160

Bravo AF: 0.190

Asia WGS AF: 0.0430 AC: 151 AN: 3478

EpiCase AF: 0.165

EpiControl AF: 0.173

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

3058+9A>G in intron 21 of HPS5: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 27.9% (1227/4398) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS; dbSNP rs2049129). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome 5 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.7
DANN	Benign	0.82
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2049129; hg19: chr11-18305333; COSMIC: COSV61687578; COSMIC: COSV61687578;