10-98419517-C-T

Variant names:

• chr10-98419517-C-T
• rs11189600
• NM_000195.5:c.1857+528G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000195.5(HPS1):​c.1857+528G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 151,718 control chromosomes in the GnomAD database, including 18,575 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (18575 hom., cov: 31)
• Consequence: HPS1 NM_000195.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.56
• Publications: 16 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5	c.1857+528G>A		intron_variant	Intron 18 of 19	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9	c.1857+528G>A		intron_variant	Intron 18 of 19	1	NM_000195.5	ENSP00000355310.4
ENSG00000289758	ENST00000699159.1	n.*1216+528G>A		intron_variant	Intron 17 of 23			ENSP00000514167.1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68840 AN: 151598 Hom.: 18512 Cov.: 31

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.565

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.415

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.454 AC: 68954 AN: 151718 Hom.: 18575 Cov.: 31 AF XY: 0.457 AC XY: 33847 AN XY: 74142

African (AFR) AF: 0.751 AC: 31103 AN: 41420

American (AMR) AF: 0.433 AC: 6613 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1429 AN: 3472

East Asian (EAS) AF: 0.565 AC: 2843 AN: 5032

South Asian (SAS) AF: 0.478 AC: 2300 AN: 4812

European-Finnish (FIN) AF: 0.285 AC: 3009 AN: 10568

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20378 AN: 67834

Other (OTH) AF: 0.413 AC: 870 AN: 2108

Alfa AF: 0.338 Hom.: 7962

Bravo AF: 0.475

Asia WGS AF: 0.518 AC: 1797 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.16
DANN	Benign	0.33
PhyloP100		-2.6
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: rs11189600; hg19: chr10-100179274;