Variant rs281865089 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000195.5(HPS1):c.1749G>C(p.Trp583Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HPS1
NM_000195.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.02

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS1	NM_000195.5 linkuse as main transcript	c.1749G>C	p.Trp583Cys	missense_variant	18/20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HPS1	ENST00000361490.9 linkuse as main transcript	c.1749G>C	p.Trp583Cys	missense_variant	18/20	1	NM_000195.5	ENSP00000355310.4	Q92902-1
ENSG00000289758	ENST00000699159.1 linkuse as main transcript	n.*1108G>C		non_coding_transcript_exon_variant	17/24			ENSP00000514167.1	A0A8V8TP71
ENSG00000289758	ENST00000699159.1 linkuse as main transcript	n.*1108G>C		3_prime_UTR_variant	17/24			ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249726

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459214

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

D;D;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

.;.;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.8

M;M;M

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-11

D;D;.

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.0020

D;D;D

Vest4

0.94

MutPred

0.72

Loss of MoRF binding (P = 0.0259);Loss of MoRF binding (P = 0.0259);Loss of MoRF binding (P = 0.0259);

MVP

0.81

MPC

0.81

ClinPred

1.0

GERP RS

5.5

Varity_R

0.95

gMVP

0.89

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over