10-98416347-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.*1217T>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 0.349 in 152,104 control chromosomes in the GnomAD database, including 10,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10412 hom., cov: 33)
  • Exomes 𝑓: 0.30 (6 hom.)
• Consequence: HPS1 NM_000195.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.141

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=-0.87).
• BP6: Variant 10-98416347-A-G is Benign according to our data. Variant chr10-98416347-A-G is described in ClinVar as [Benign]. Clinvar id is 298308.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5	c.*1217T>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.*1217T>C		3_prime_UTR_variant	20/20	1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53023 AN: 151838 Hom.: 10399 Cov.: 33

Gnomad AFR AF: 0.527

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.320

GnomAD4 exome AF: 0.297 AC: 44 AN: 148 Hom.: 6 Cov.: 0 AF XY: 0.333 AC XY: 28 AN XY: 84

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.301

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.349 AC: 53084 AN: 151956 Hom.: 10412 Cov.: 33 AF XY: 0.350 AC XY: 25978 AN XY: 74304

Gnomad4 AFR AF: 0.527

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.414

Gnomad4 SAS AF: 0.494

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.318

Alfa AF: 0.301 Hom.: 964

Bravo AF: 0.362

Asia WGS AF: 0.451 AC: 1566 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 12, 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	-0.87
Cadd	Benign	1.6
Dann	Benign	0.39

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: rs3830025; hg19: chr10-100176104;