rs7128146

Positions:

• chr11-18297732-G-T

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.1165-15C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,608,254 control chromosomes in the GnomAD database, including 10,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1572 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9160 hom.)
• Consequence: HPS5 NM_181507.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.168

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=-0.85).
• BP6: Variant 11-18297732-G-T is Benign according to our data. Variant chr11-18297732-G-T is described in ClinVar as [Benign]. Clinvar id is 178779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2	c.1165-15C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8	c.1165-15C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_181507.2	P1
HPS5	ENST00000396253.7	c.823-15C>A		splice_polypyrimidine_tract_variant, intron_variant		1
HPS5	ENST00000438420.6	c.823-15C>A		splice_polypyrimidine_tract_variant, intron_variant		1
HPS5	ENST00000531848.1	c.823-15C>A		splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21135 AN: 152026 Hom.: 1569 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.151

GnomAD3 exomes AF: 0.136 AC: 34132 AN: 250574 Hom.: 2722 AF XY: 0.131 AC XY: 17740 AN XY: 135520

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.105 AC: 153449 AN: 1456110 Hom.: 9160 Cov.: 30 AF XY: 0.106 AC XY: 76697 AN XY: 724814

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.0920

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.139 AC: 21149 AN: 152144 Hom.: 1572 Cov.: 32 AF XY: 0.142 AC XY: 10561 AN XY: 74388

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.150

Alfa AF: 0.128 Hom.: 324

Bravo AF: 0.140

Asia WGS AF: 0.141 AC: 492 AN: 3478

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	1165-15C>A in intron 10 of HPS5: This variant is not expected to have clinical s ignificance because it has been identified in 19.6% (860/4396) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs7128146). -
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	-0.85
CADD	Benign	0.73
DANN	Benign	0.37

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: rs7128146; hg19: chr11-18319279; COSMIC: COSV61687455; COSMIC: COSV61687455;