Genetic Variant HPS1:c.1335+48G>A (chr10-98425493-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000195.5(HPS1):c.1335+48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0898 in 1,564,768 control chromosomes in the GnomAD database, including 6,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.099 ( 790 hom., cov: 33)

Exomes 𝑓: 0.089 ( 6052 hom. )

Consequence

HPS1
NM_000195.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.02

Variant links:

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 links:

ENSG00000289758 (HGNC:):

ENSG00000289758 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 10-98425493-C-T is Benign according to our data. Variant chr10-98425493-C-T is described in ClinVar as [Benign]. Clinvar id is 255499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5 link	c.1335+48G>A		intron_variant	Intron 13 of 19	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9 link	c.1335+48G>A		intron_variant	Intron 13 of 19	1	NM_000195.5	ENSP00000355310.4		Q92902-1
ENSG00000289758	ENST00000699159.1 link	n.*694+48G>A		intron_variant	Intron 12 of 23			ENSP00000514167.1		A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.0990

AC:

15063

AN:

152176

Hom.:

788

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.125

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.171

Gnomad SAS

AF:

0.0443

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0843

Gnomad OTH

AF:

0.111

GnomAD3 exomes

AF:

0.106

AC:

19967

AN:

188278

Hom.:

1286

AF XY:

0.0998

AC XY:

10029

AN XY:

100448

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.123

Gnomad EAS exome

AF:

0.190

Gnomad SAS exome

AF:

0.0406

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0881

Gnomad OTH exome

AF:

0.111

GnomAD4 exome

AF:

0.0888

AC:

125486

AN:

1412474

Hom.:

6052

Cov.:

AF XY:

0.0874

AC XY:

61120

AN XY:

699396

show subpopulations

Gnomad4 AFR exome

AF:

0.110

Gnomad4 AMR exome

AF:

0.160

Gnomad4 ASJ exome

AF:

0.121

Gnomad4 EAS exome

AF:

0.164

Gnomad4 SAS exome

AF:

0.0422

Gnomad4 FIN exome

AF:

0.113

Gnomad4 NFE exome

AF:

0.0840

Gnomad4 OTH exome

AF:

0.0976

GnomAD4 genome

AF:

0.0990

AC:

15084

AN:

152294

Hom.:

790

Cov.:

AF XY:

0.102

AC XY:

7588

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.105

Gnomad4 AMR

AF:

0.126

Gnomad4 ASJ

AF:

0.135

Gnomad4 EAS

AF:

0.172

Gnomad4 SAS

AF:

0.0443

Gnomad4 FIN

AF:

0.109

Gnomad4 NFE

AF:

0.0842

Gnomad4 OTH

AF:

0.109

Alfa

AF:

0.0970

Hom.:

199

Bravo

AF:

0.103

Asia WGS

AF:

0.102

AC:

358

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome 1

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.5

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over