10-98423758-G-C

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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• 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

Sel.	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	Q92902-1
	HPS1	NM_001322477.2		c.1527C>G	p.Leu509Leu	synonymous	Exon 15 of 20	NP_001309406.1	Q92902-1

Ensembl Transcripts

Sel.	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	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*886C>G		non_coding_transcript_exon	Exon 14 of 19	ENSP00000514163.1	A0A8V8TP71
	ENSG00000289758	ENST00000699159.1		n.*886C>G		non_coding_transcript_exon	Exon 14 of 24	ENSP00000514167.1	A0A8V8TP71

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hermansky-Pudlak syndrome (1)
-	-	1	Hermansky-Pudlak syndrome 1 (1)
-	-	1	not specified (1)

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;