rs2296434

Variant summary

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

The NM_000195.5(HPS1):ā€‹c.1472C>Gā€‹(p.Pro491Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 1,613,882 control chromosomes in the GnomAD database, including 7,326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P491H) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.10 ( 830 hom., cov: 32)
Exomes š‘“: 0.090 ( 6496 hom. )

Consequence

HPS1
NM_000195.5 missense

Scores

6
12

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.75
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]

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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 (MetaRNN=0.0017885268).
BP6
Variant 10-98423813-G-C is Benign according to our data. Variant chr10-98423813-G-C is described in ClinVar as [Benign]. Clinvar id is 21094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98423813-G-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HPS1NM_000195.5 linkuse as main transcriptc.1472C>G p.Pro491Arg missense_variant 15/20 ENST00000361490.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HPS1ENST00000361490.9 linkuse as main transcriptc.1472C>G p.Pro491Arg missense_variant 15/201 NM_000195.5 P1Q92902-1

Frequencies

GnomAD3 genomes
AF:
0.101
AC:
15373
AN:
152114
Hom.:
827
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.105
Gnomad AMI
AF:
0.0702
Gnomad AMR
AF:
0.126
Gnomad ASJ
AF:
0.128
Gnomad EAS
AF:
0.170
Gnomad SAS
AF:
0.0445
Gnomad FIN
AF:
0.134
Gnomad MID
AF:
0.120
Gnomad NFE
AF:
0.0851
Gnomad OTH
AF:
0.113
GnomAD3 exomes
AF:
0.107
AC:
26818
AN:
251010
Hom.:
1717
AF XY:
0.101
AC XY:
13658
AN XY:
135740
show subpopulations
Gnomad AFR exome
AF:
0.107
Gnomad AMR exome
AF:
0.164
Gnomad ASJ exome
AF:
0.121
Gnomad EAS exome
AF:
0.186
Gnomad SAS exome
AF:
0.0402
Gnomad FIN exome
AF:
0.129
Gnomad NFE exome
AF:
0.0888
Gnomad OTH exome
AF:
0.112
GnomAD4 exome
AF:
0.0903
AC:
132043
AN:
1461650
Hom.:
6496
Cov.:
34
AF XY:
0.0887
AC XY:
64518
AN XY:
727128
show subpopulations
Gnomad4 AFR exome
AF:
0.110
Gnomad4 AMR exome
AF:
0.162
Gnomad4 ASJ exome
AF:
0.120
Gnomad4 EAS exome
AF:
0.161
Gnomad4 SAS exome
AF:
0.0424
Gnomad4 FIN exome
AF:
0.129
Gnomad4 NFE exome
AF:
0.0848
Gnomad4 OTH exome
AF:
0.0991
GnomAD4 genome
AF:
0.101
AC:
15395
AN:
152232
Hom.:
830
Cov.:
32
AF XY:
0.105
AC XY:
7811
AN XY:
74408
show subpopulations
Gnomad4 AFR
AF:
0.105
Gnomad4 AMR
AF:
0.126
Gnomad4 ASJ
AF:
0.128
Gnomad4 EAS
AF:
0.171
Gnomad4 SAS
AF:
0.0446
Gnomad4 FIN
AF:
0.134
Gnomad4 NFE
AF:
0.0851
Gnomad4 OTH
AF:
0.111
Alfa
AF:
0.0832
Hom.:
463
Bravo
AF:
0.104
TwinsUK
AF:
0.0774
AC:
287
ALSPAC
AF:
0.0877
AC:
338
ESP6500AA
AF:
0.110
AC:
484
ESP6500EA
AF:
0.0845
AC:
727
ExAC
AF:
0.104
AC:
12650
EpiCase
AF:
0.0884
EpiControl
AF:
0.0872

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 21, 2013Pro491Arg in exon 15 of HPS1: This variant is not expected to have clinical sign ificance because it has been identified in 11.0% (484/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2296434). -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Hermansky-Pudlak syndrome 1 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 10, 2021- -
Hermansky-Pudlak syndrome Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.38
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T;T;T;T
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.87
.;.;D;D
MetaRNN
Benign
0.0018
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.7
M;M;M;.
MutationTaster
Benign
0.0061
P;P
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-2.1
N;N;.;D
REVEL
Benign
0.16
Sift
Benign
0.070
T;T;.;D
Sift4G
Benign
0.095
T;T;T;T
Vest4
0.21
MPC
0.65
ClinPred
0.026
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.057
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs2296434; hg19: chr10-100183570; COSMIC: COSV57267549; COSMIC: COSV57267549; API