rs1894704

Positions:

Variant summary

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

The NM_022081.6(HPS4):c.1875G>T(p.Gln625His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.909 in 1,613,816 control chromosomes in the GnomAD database, including 670,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 57534 hom., cov: 33)

Exomes 𝑓: 0.91 ( 613039 hom. )

Consequence

HPS4
NM_022081.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.03

Variant links:

Genes affected

HPS4 (HGNC:15844): (HPS4 biogenesis of lysosomal organelles complex 3 subunit 2) This gene encodes a protein component of biogenesis of lysosome-related organelles complexes (BLOC). BLOC complexes are important for the formation of endosomal-lysosomal organelles such as melanosomes and platelet dense granules. Mutations in this gene result in subtype 4 of Hermansky-Pudlak syndrome, a form of albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

HPS4 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=8.3816076E-7).

BP6

Variant 22-26457939-C-A is Benign according to our data. Variant chr22-26457939-C-A is described in ClinVar as [Benign]. Clinvar id is 163670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-26457939-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS4	NM_022081.6 linkuse as main transcript	c.1875G>T	p.Gln625His	missense_variant	13/14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7 linkuse as main transcript	c.1875G>T	p.Gln625His	missense_variant	13/14	1	NM_022081.6	ENSP00000381213	P2	Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.865

AC:

131601

AN:

152140

Hom.:

57522

Cov.:

show subpopulations

Gnomad AFR

AF:

0.754

Gnomad AMI

AF:

0.841

Gnomad AMR

AF:

0.784

Gnomad ASJ

AF:

0.952

Gnomad EAS

AF:

0.787

Gnomad SAS

AF:

0.913

Gnomad FIN

AF:

0.982

Gnomad MID

AF:

0.908

Gnomad NFE

AF:

0.931

Gnomad OTH

AF:

0.872

GnomAD3 exomes

AF:

0.877

AC:

220034

AN:

250860

Hom.:

97766

AF XY:

0.890

AC XY:

120718

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.749

Gnomad AMR exome

AF:

0.683

Gnomad ASJ exome

AF:

0.960

Gnomad EAS exome

AF:

0.793

Gnomad SAS exome

AF:

0.922

Gnomad FIN exome

AF:

0.979

Gnomad NFE exome

AF:

0.928

Gnomad OTH exome

AF:

0.900

GnomAD4 exome

AF:

0.914

AC:

1335791

AN:

1461558

Hom.:

613039

Cov.:

AF XY:

0.916

AC XY:

666194

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.749

Gnomad4 AMR exome

AF:

0.698

Gnomad4 ASJ exome

AF:

0.957

Gnomad4 EAS exome

AF:

0.769

Gnomad4 SAS exome

AF:

0.927

Gnomad4 FIN exome

AF:

0.973

Gnomad4 NFE exome

AF:

0.928

Gnomad4 OTH exome

AF:

0.906

GnomAD4 genome

AF:

0.865

AC:

131662

AN:

152258

Hom.:

57534

Cov.:

AF XY:

0.865

AC XY:

64394

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.753

Gnomad4 AMR

AF:

0.784

Gnomad4 ASJ

AF:

0.952

Gnomad4 EAS

AF:

0.787

Gnomad4 SAS

AF:

0.914

Gnomad4 FIN

AF:

0.982

Gnomad4 NFE

AF:

0.931

Gnomad4 OTH

AF:

0.870

Alfa

AF:

0.915

Hom.:

154897

Bravo

AF:

0.842

TwinsUK

AF:

0.926

AC:

3432

ALSPAC

AF:

0.922

AC:

3552

ESP6500AA

AF:

0.753

AC:

3317

ESP6500EA

AF:

0.928

AC:

7979

ExAC

AF:

0.881

AC:

107017

Asia WGS

AF:

0.824

AC:

2868

AN:

3478

EpiCase

AF:

0.932

EpiControl

AF:

0.926

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Gln625His in exon 13 of HPS4: This variant is not expected to have clinical sign ificance because it has been identified in 24.7% (1089/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs1894704). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hermansky-Pudlak syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hermansky-Pudlak syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.54

.;T;T

MetaRNN

Benign

8.4e-7

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;.;M

MutationTaster

Benign

0.85

P;P;P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.022

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.35

T;T;T

Polyphen

0.83

P;P;P

Vest4

0.11

MutPred

0.16

Loss of helix (P = 0.0626);.;Loss of helix (P = 0.0626);

MPC

0.18

ClinPred

0.012

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.055

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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