chr10-98443230-A-G

Position:

chr10-98443230-A-G

Variant summary

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

The NM_000195.5(HPS1):c.11T>C(p.Val4Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,613,178 control chromosomes in the GnomAD database, including 791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.036 ( 124 hom., cov: 32)

Exomes 𝑓: 0.025 ( 667 hom. )

Consequence

HPS1
NM_000195.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.98

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004116535).

BP6

Variant 10-98443230-A-G is Benign according to our data. Variant chr10-98443230-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 163667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98443230-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5 linkuse as main transcript	c.11T>C	p.Val4Ala	missense_variant	3/20	ENST00000361490.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9 linkuse as main transcript	c.11T>C	p.Val4Ala	missense_variant	3/20	1	NM_000195.5	P1	Q92902-1

Frequencies

GnomAD3 genomes

AF:

0.0362

AC:

5507

AN:

151990

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0606

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0193

Gnomad ASJ

AF:

0.0380

Gnomad EAS

AF:

0.0112

Gnomad SAS

AF:

0.0554

Gnomad FIN

AF:

0.0477

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0246

Gnomad OTH

AF:

0.0283

GnomAD3 exomes

AF:

0.0313

AC:

7864

AN:

251482

Hom.:

175

AF XY:

0.0323

AC XY:

4390

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0615

Gnomad AMR exome

AF:

0.0151

Gnomad ASJ exome

AF:

0.0378

Gnomad EAS exome

AF:

0.00827

Gnomad SAS exome

AF:

0.0517

Gnomad FIN exome

AF:

0.0499

Gnomad NFE exome

AF:

0.0261

Gnomad OTH exome

AF:

0.0296

GnomAD4 exome

AF:

0.0249

AC:

36452

AN:

1461070

Hom.:

667

Cov.:

AF XY:

0.0258

AC XY:

18749

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.0617

Gnomad4 AMR exome

AF:

0.0151

Gnomad4 ASJ exome

AF:

0.0372

Gnomad4 EAS exome

AF:

0.00990

Gnomad4 SAS exome

AF:

0.0497

Gnomad4 FIN exome

AF:

0.0511

Gnomad4 NFE exome

AF:

0.0209

Gnomad4 OTH exome

AF:

0.0300

GnomAD4 genome

AF:

0.0363

AC:

5516

AN:

152108

Hom.:

124

Cov.:

AF XY:

0.0376

AC XY:

2797

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0608

Gnomad4 AMR

AF:

0.0192

Gnomad4 ASJ

AF:

0.0380

Gnomad4 EAS

AF:

0.0110

Gnomad4 SAS

AF:

0.0548

Gnomad4 FIN

AF:

0.0477

Gnomad4 NFE

AF:

0.0245

Gnomad4 OTH

AF:

0.0280

Alfa

AF:

0.0258

Hom.:

Bravo

AF:

0.0324

TwinsUK

AF:

0.0191

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.0629

AC:

277

ESP6500EA

AF:

0.0215

AC:

185

ExAC

AF:

0.0333

AC:

4037

Asia WGS

AF:

0.0390

AC:

136

AN:

3478

EpiCase

AF:

0.0245

EpiControl

AF:

0.0220

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Val4Ala in exon 3 of HPS1: This variant is not expected to have clinical signifi cance because it has been identified in 6.3% (277/4406) of African American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS; dbSNP rs58548334). -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hermansky-Pudlak syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 26, 2021

- -

Hermansky-Pudlak syndrome 1

Benign:1

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 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

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.57

.;.;T;T

MetaRNN

Benign

0.0041

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.5

M;M;M;M

MutationTaster

Benign

0.79

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.7

D;D;.;N

REVEL

Benign

0.18

Sift

Uncertain

0.011

D;D;.;D

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.97

D;D;D;P

Vest4

0.21

MPC

0.45

ClinPred

0.020

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.55

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