rs112544050

chr10-98417552-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000195.5(HPS1):c.*12C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00411 in 1,606,024 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (18 hom.)
• Consequence: HPS1 NM_000195.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.16

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-98417552-G-A is Benign according to our data. Variant chr10-98417552-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98417552-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00338 (514/152246) while in subpopulation NFE AF= 0.00506 (344/67986). AF 95% confidence interval is 0.00462. There are 3 homozygotes in gnomad4. There are 246 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5	c.*12C>T		3_prime_UTR_variant	20/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.*12C>T		3_prime_UTR_variant	20/20	1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152128 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00294 AC: 712 AN: 242288 Hom.: 1 AF XY: 0.00273 AC XY: 360 AN XY: 131772

Gnomad AFR exome AF: 0.000589

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000300

Gnomad FIN exome AF: 0.00264

Gnomad NFE exome AF: 0.00505

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00418 AC: 6083 AN: 1453778 Hom.: 18 Cov.: 31 AF XY: 0.00399 AC XY: 2886 AN XY: 722714

Gnomad4 AFR exome AF: 0.000570

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000409

Gnomad4 FIN exome AF: 0.00257

Gnomad4 NFE exome AF: 0.00508

Gnomad4 OTH exome AF: 0.00294

GnomAD4 genome AF: 0.00338 AC: 514 AN: 152246 Hom.: 3 Cov.: 33 AF XY: 0.00330 AC XY: 246 AN XY: 74438

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00506

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00334 Hom.: 0

Bravo AF: 0.00303

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hermansky-Pudlak syndrome 1 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.11
Dann	Benign	0.82

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: rs112544050; hg19: chr10-100177309;