rs1739

Positions:

• chr10-98416582-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000195.5(HPS1):​c.*982T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 152,282 control chromosomes in the GnomAD database, including 18,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (18070 hom., cov: 33)
  • Exomes 𝑓: 0.41 (17 hom.)
• Consequence: HPS1 NM_000195.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0520

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 10-98416582-A-G is Benign according to our data. Variant chr10-98416582-A-G is described in ClinVar as [Benign]. Clinvar id is 298314.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5	c.*982T>C		3_prime_UTR_variant	20/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.*982T>C		3_prime_UTR_variant	20/20	1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.461 AC: 69988 AN: 151968 Hom.: 18029 Cov.: 33

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.443

GnomAD4 exome AF: 0.413 AC: 81 AN: 196 Hom.: 17 Cov.: 0 AF XY: 0.474 AC XY: 54 AN XY: 114

Gnomad4 EAS exome AF: 0.397

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.417

Gnomad4 OTH exome AF: 0.583

GnomAD4 genome AF: 0.461 AC: 70082 AN: 152086 Hom.: 18070 Cov.: 33 AF XY: 0.464 AC XY: 34465 AN XY: 74346

Gnomad4 AFR AF: 0.687

Gnomad4 AMR AF: 0.457

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.659

Gnomad4 SAS AF: 0.527

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.440

Alfa AF: 0.369 Hom.: 11230

Bravo AF: 0.477

Asia WGS AF: 0.569 AC: 1976 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.92
CADD	Benign	2.3
DANN	Benign	0.42

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: rs1739; hg19: chr10-100176339; COSMIC: COSV105206670; COSMIC: COSV105206670;