11-18283786-T-C

Variant summary

Our verdict is Benign. Variant got -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:5
• Conservation: PhyloP100: -0.526

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 (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 id 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/exons	MANE	UniProt
HPS5	NM_181507.2	c.3058+9A>G		intron_variant		ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8	c.3058+9A>G		intron_variant		1	NM_181507.2	P1

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

GnomAD3 exomes AF: 0.147 AC: 36894 AN: 250774 Hom.: 3293 AF XY: 0.145 AC XY: 19720 AN XY: 135628

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 SAS exome AF: 0.0747

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

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.0873

Gnomad4 ASJ exome AF: 0.163

Gnomad4 EAS exome AF: 0.000835

Gnomad4 SAS exome AF: 0.0775

Gnomad4 FIN exome AF: 0.211

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.161

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

Gnomad4 AFR AF: 0.285

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0604

Gnomad4 FIN AF: 0.203

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.173

Alfa AF: 0.170 Hom.: 4523

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hermansky-Pudlak syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	7.7
Dann	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs2049129; hg19: chr11-18305333; COSMIC: COSV61687578; COSMIC: COSV61687578;