rs11591594

chr10-98434126-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000195.5(HPS1):c.399-35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,538,246 control chromosomes in the GnomAD database, including 20,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1516 hom., cov: 31)
  • Exomes 𝑓: 0.16 (19273 hom.)
• Consequence: HPS1 NM_000195.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.39

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=-0.88).
• BP6: Variant 10-98434126-C-T is Benign according to our data. Variant chr10-98434126-C-T is described in ClinVar as [Benign]. Clinvar id is 255503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5	c.399-35G>A		intron_variant		ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.399-35G>A		intron_variant		1	NM_000195.5	P1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19501 AN: 152004 Hom.: 1518 Cov.: 31

Gnomad AFR AF: 0.0609

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0925

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.143 AC: 20465 AN: 142816 Hom.: 1709 AF XY: 0.151 AC XY: 11616 AN XY: 76858

Gnomad AFR exome AF: 0.0537

Gnomad AMR exome AF: 0.0702

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.117

Gnomad SAS exome AF: 0.205

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.163 AC: 226344 AN: 1386124 Hom.: 19273 Cov.: 32 AF XY: 0.165 AC XY: 112852 AN XY: 683668

Gnomad4 AFR exome AF: 0.0556

Gnomad4 AMR exome AF: 0.0717

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.0879

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.128 AC: 19504 AN: 152122 Hom.: 1516 Cov.: 31 AF XY: 0.129 AC XY: 9562 AN XY: 74344

Gnomad4 AFR AF: 0.0609

Gnomad4 AMR AF: 0.0924

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.127

Alfa AF: 0.143 Hom.: 387

Bravo AF: 0.117

Asia WGS AF: 0.140 AC: 484 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2018

- -

Hermansky-Pudlak syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	1.2
Dann	Benign	0.44
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8

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: rs11591594; hg19: chr10-100193883;