rs12571249

Variant names:

• chr10-98427202-A-G
• rs12571249
• NM_000195.5:c.987+13T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000195.5(HPS1):​c.987+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,550,062 control chromosomes in the GnomAD database, including 1,043 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (363 hom., cov: 33)
  • Exomes 𝑓: 0.015 (680 hom.)
• Consequence: HPS1 NM_000195.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.962

Genes affected

HPS1 (HGNC:5163): (HPS1 biogenesis of lysosomal organelles complex 3 subunit 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is a component of three different protein complexes termed biogenesis of lysosome-related organelles complex (BLOC)-3, BLOC4, and BLOC5. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 1. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on chromosome 22. [provided by RefSeq, Aug 2015]

ENSG00000289758 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 10-98427202-A-G is Benign according to our data. Variant chr10-98427202-A-G is described in ClinVar as [Benign]. Clinvar id is 255506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5	c.987+13T>C		intron_variant	Intron 11 of 19	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9	c.987+13T>C		intron_variant	Intron 11 of 19	1	NM_000195.5	ENSP00000355310.4
ENSG00000289758	ENST00000699159.1	n.*346+13T>C		intron_variant	Intron 10 of 23			ENSP00000514167.1

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6801 AN: 152218 Hom.: 362 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.0746

Gnomad SAS AF: 0.0856

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00708

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.0283 AC: 4416 AN: 156290 Hom.: 180 AF XY: 0.0296 AC XY: 2433 AN XY: 82228

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.00987

Gnomad ASJ exome AF: 0.00720

Gnomad EAS exome AF: 0.0801

Gnomad SAS exome AF: 0.0685

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.00659

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0150 AC: 20999 AN: 1397726 Hom.: 680 Cov.: 30 AF XY: 0.0162 AC XY: 11188 AN XY: 689522

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.0562

Gnomad4 SAS exome AF: 0.0680

Gnomad4 FIN exome AF: 0.000937

Gnomad4 NFE exome AF: 0.00677

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0448 AC: 6822 AN: 152336 Hom.: 363 Cov.: 33 AF XY: 0.0443 AC XY: 3300 AN XY: 74492

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0225

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.0745

Gnomad4 SAS AF: 0.0854

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00709

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0195 Hom.: 26

Bravo AF: 0.0487

Asia WGS AF: 0.0930 AC: 322 AN: 3478

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

987+13T>C in intron 11 of HPS1: 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 10.8% (448/4134) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS; dbSNP rs12571249). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome 1 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	-0.92
CADD	Benign	0.015
DANN	Benign	0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12571249; hg19: chr10-100186959;