10-98429811-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000195.5(HPS1):c.847G>C(p.Gly283Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G283W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

HPS1
NM_000195.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -1.55

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009726554).

BP6

Variant 10-98429811-C-G is Benign according to our data. Variant chr10-98429811-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1188296.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr10-98429811-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5 link	c.847G>C	p.Gly283Arg	missense_variant	Exon 9 of 20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9 link	c.847G>C	p.Gly283Arg	missense_variant	Exon 9 of 20	1	NM_000195.5	ENSP00000355310.4		Q92902-1
ENSG00000289758	ENST00000699159.1 link	n.*227-169G>C		intron_variant	Intron 8 of 23			ENSP00000514167.1		A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000386

AC:

AN:

251054

Hom.:

AF XY:

0.000405

AC XY:

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.000801

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000870

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000370

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000316

AC:

462

AN:

1461492

Hom.:

Cov.:

AF XY:

0.000320

AC XY:

233

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.0000566

Gnomad4 NFE exome

AF:

0.000311

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000519

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000139

Hom.:

495

Bravo

AF:

0.000491

ExAC

AF:

0.000412

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Mar 27, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome

Uncertain:1

Jan 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome 1

Uncertain:1

Mar 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.0010

DANN

Benign

0.40

DEOGEN2

Benign

0.052

T;T;T;.

Eigen

Benign

-2.5

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.24

.;.;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.0097

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.020

N;N;.;N

REVEL

Benign

0.013

Sift

Benign

0.68

T;T;.;T

Sift4G

Benign

0.57

T;T;T;T

Polyphen

0.0020

B;B;B;B

Vest4

0.11

MVP

0.085

MPC

0.17

ClinPred

0.00098

GERP RS

-5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.030

gMVP

0.18

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