NM_000195.5:c.1397+8G>T

Variant names:

Variant summary

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

The NM_000195.5(HPS1):c.1397+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,605,012 control chromosomes in the GnomAD database, including 51,037 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4112 hom., cov: 33)

Exomes 𝑓: 0.25 ( 46925 hom. )

Consequence

HPS1
NM_000195.5 splice_region, intron

Scores

Splicing: ADA: 0.0006200

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.466

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=-0.79).

BP6

Variant 10-98424305-C-A is Benign according to our data. Variant chr10-98424305-C-A is described in ClinVar as [Benign]. Clinvar id is 163664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5 link	c.1397+8G>T		splice_region_variant, intron_variant	Intron 14 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.1397+8G>T		splice_region_variant, intron_variant	Intron 14 of 19	1	NM_000195.5	ENSP00000355310.4		Q92902-1
ENSG00000289758	ENST00000699159.1 link	n.*756+8G>T		splice_region_variant, intron_variant	Intron 13 of 23			ENSP00000514167.1		A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33210

AN:

151912

Hom.:

4108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.262

Gnomad AMR

AF:

0.281

Gnomad ASJ

AF:

0.311

Gnomad EAS

AF:

0.369

Gnomad SAS

AF:

0.396

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.236

Gnomad OTH

AF:

0.216

GnomAD3 exomes

AF:

0.264

AC:

64703

AN:

245248

Hom.:

9008

AF XY:

0.270

AC XY:

35758

AN XY:

132404

show subpopulations

Gnomad AFR exome

AF:

0.113

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.310

Gnomad EAS exome

AF:

0.345

Gnomad SAS exome

AF:

0.394

Gnomad FIN exome

AF:

0.224

Gnomad NFE exome

AF:

0.231

Gnomad OTH exome

AF:

0.256

GnomAD4 exome

AF:

0.247

AC:

359167

AN:

1452978

Hom.:

46925

Cov.:

AF XY:

0.252

AC XY:

182402

AN XY:

722744

show subpopulations

Gnomad4 AFR exome

AF:

0.117

Gnomad4 AMR exome

AF:

0.297

Gnomad4 ASJ exome

AF:

0.310

Gnomad4 EAS exome

AF:

0.365

Gnomad4 SAS exome

AF:

0.404

Gnomad4 FIN exome

AF:

0.230

Gnomad4 NFE exome

AF:

0.232

Gnomad4 OTH exome

AF:

0.253

GnomAD4 genome

AF:

0.218

AC:

33219

AN:

152034

Hom.:

4112

Cov.:

AF XY:

0.223

AC XY:

16574

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.118

Gnomad4 AMR

AF:

0.281

Gnomad4 ASJ

AF:

0.311

Gnomad4 EAS

AF:

0.369

Gnomad4 SAS

AF:

0.396

Gnomad4 FIN

AF:

0.223

Gnomad4 NFE

AF:

0.236

Gnomad4 OTH

AF:

0.214

Alfa

AF:

0.223

Hom.:

1777

Bravo

AF:

0.214

Asia WGS

AF:

0.332

AC:

1153

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 26, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1397+8G>T in intron 14 of HPS1: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 20.4% (1753/8600) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs2296433). -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome 1

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hermansky-Pudlak syndrome

Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.52

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00062

dbscSNV1_RF

Benign

0.012

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