NM_000195.5:c.1527C>G

Variant names:

• chr10-98423758-G-C
• rs17109850
• NM_000195.5:c.1527C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000195.5(HPS1):​c.1527C>G​(p.Leu509Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,614,126 control chromosomes in the GnomAD database, including 405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L509L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (36 hom., cov: 32)
  • Exomes 𝑓: 0.011 (369 hom.)
• Consequence: HPS1 NM_000195.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.50
• Publications: 10 publications found

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]

HPS1 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289758 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 10-98423758-G-C is Benign according to our data. Variant chr10-98423758-G-C is described in ClinVar as Benign. ClinVar VariationId is 255501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0768 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000195.5. 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
	HPS1	NM_000195.5	MANE Select	c.1527C>G	p.Leu509Leu	synonymous	Exon 15 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.1527C>G	p.Leu509Leu	synonymous	Exon 15 of 20	NP_001309405.1
	HPS1	NM_001322477.2		c.1527C>G	p.Leu509Leu	synonymous	Exon 15 of 20	NP_001309406.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.1527C>G	p.Leu509Leu	synonymous	Exon 15 of 20	ENSP00000355310.4
	HPS1	ENST00000467246.5	TSL:1	n.*886C>G		non_coding_transcript_exon	Exon 14 of 19	ENSP00000514163.1
	ENSG00000289758	ENST00000699159.1		n.*886C>G		non_coding_transcript_exon	Exon 14 of 24	ENSP00000514167.1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2310 AN: 152224 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0374

Gnomad SAS AF: 0.0836

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00619

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0168 AC: 4212 AN: 251230 AF XY: 0.0191

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0393

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00536

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0111 AC: 16191 AN: 1461784 Hom.: 369 Cov.: 33 AF XY: 0.0128 AC XY: 9282 AN XY: 727196

African (AFR) AF: 0.0308 AC: 1031 AN: 33480

American (AMR) AF: 0.00478 AC: 214 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.0269 AC: 1066 AN: 39700

South Asian (SAS) AF: 0.0688 AC: 5933 AN: 86250

European-Finnish (FIN) AF: 0.000825 AC: 44 AN: 53342

Middle Eastern (MID) AF: 0.00992 AC: 57 AN: 5748

European-Non Finnish (NFE) AF: 0.00625 AC: 6948 AN: 1112010

Other (OTH) AF: 0.0147 AC: 888 AN: 60394

GnomAD4 genome AF: 0.0152 AC: 2308 AN: 152342 Hom.: 36 Cov.: 32 AF XY: 0.0157 AC XY: 1168 AN XY: 74492

African (AFR) AF: 0.0268 AC: 1114 AN: 41590

American (AMR) AF: 0.00882 AC: 135 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.0373 AC: 193 AN: 5178

South Asian (SAS) AF: 0.0835 AC: 403 AN: 4828

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00619 AC: 421 AN: 68022

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00807 Hom.: 4

Bravo AF: 0.0144

Asia WGS AF: 0.0700 AC: 244 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00581

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hermansky-Pudlak syndrome Benign:1

Nov 26, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.2
DANN	Benign	0.55
PhyloP100		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17109850; hg19: chr10-100183515;