10-98423758-G-C

Position:

• chr10-98423758-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000195.5(HPS1):​c.1527C>G​(p.Leu509=) 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 (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS1	NM_000195.5	c.1527C>G	p.Leu509=	synonymous_variant	15/20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9	c.1527C>G	p.Leu509=	synonymous_variant	15/20	1	NM_000195.5	ENSP00000355310	P1

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

GnomAD3 exomes AF: 0.0168 AC: 4212 AN: 251230 Hom.: 132 AF XY: 0.0191 AC XY: 2594 AN XY: 135826

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 SAS exome AF: 0.0716

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

Gnomad4 AFR exome AF: 0.0308

Gnomad4 AMR exome AF: 0.00478

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0269

Gnomad4 SAS exome AF: 0.0688

Gnomad4 FIN exome AF: 0.000825

Gnomad4 NFE exome AF: 0.00625

Gnomad4 OTH exome AF: 0.0147

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

Gnomad4 AFR AF: 0.0268

Gnomad4 AMR AF: 0.00882

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0373

Gnomad4 SAS AF: 0.0835

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00619

Gnomad4 OTH AF: 0.0147

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hermansky-Pudlak syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 26, 2019

- -

Hermansky-Pudlak syndrome 1 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	-0.59
CADD	Benign	5.2
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs17109850; hg19: chr10-100183515;