NM_022081.6:c.1875G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict 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:8

Conservation

PhyloP100: 2.03

Publications

33 publications found

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 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
Hermansky-Pudlak syndrome with pulmonary fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HPS4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 163670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
HPS4	NM_022081.6 link	c.1875G>T	p.Gln625His	missense_variant	Exon 13 of 14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7 link	c.1875G>T	p.Gln625His	missense_variant	Exon 13 of 14	1	NM_022081.6	ENSP00000381213.2		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

GnomAD2 exomes

AF:

0.877

AC:

220034

AN:

250860

AF XY:

0.890

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 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

African (AFR)

AF:

0.749

AC:

25080

AN:

33470

American (AMR)

AF:

0.698

AC:

31225

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.957

AC:

25021

AN:

26136

East Asian (EAS)

AF:

0.769

AC:

30513

AN:

39698

South Asian (SAS)

AF:

0.927

AC:

79942

AN:

86248

European-Finnish (FIN)

AF:

0.973

AC:

51799

AN:

53216

Middle Eastern (MID)

AF:

0.914

AC:

5268

AN:

5766

European-Non Finnish (NFE)

AF:

0.928

AC:

1032212

AN:

1111924

Other (OTH)

AF:

0.906

AC:

54731

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

6580

13160

19741

26321

32901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21490

42980

64470

85960

107450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.865

AC:

131662

AN:

152258

Hom.:

57534

Cov.:

AF XY:

0.865

AC XY:

64394

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.753

AC:

31280

AN:

41528

American (AMR)

AF:

0.784

AC:

11993

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.952

AC:

3307

AN:

3472

East Asian (EAS)

AF:

0.787

AC:

4066

AN:

5164

South Asian (SAS)

AF:

0.914

AC:

4412

AN:

4828

European-Finnish (FIN)

AF:

0.982

AC:

10431

AN:

10624

Middle Eastern (MID)

AF:

0.905

AC:

266

AN:

294

European-Non Finnish (NFE)

AF:

0.931

AC:

63301

AN:

68028

Other (OTH)

AF:

0.870

AC:

1839

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

862

1724

2585

3447

4309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

892

1784

2676

3568

4460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.908

Hom.:

282442

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Feb 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome 4

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

2.0

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over