rs34962745

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_022081.6(HPS4):c.751A>T(p.Thr251Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00924 in 1,613,952 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0069 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0095 ( 83 hom. )

Consequence

HPS4
NM_022081.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 4.57

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051202774).

BP6

Variant 22-26465507-T-A is Benign according to our data. Variant chr22-26465507-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 341016.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00694 (1057/152208) while in subpopulation AMR AF = 0.0124 (189/15298). AF 95% confidence interval is 0.0109. There are 9 homozygotes in GnomAd4. There are 468 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6 link	c.751A>T	p.Thr251Ser	missense_variant	Exon 10 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.751A>T	p.Thr251Ser	missense_variant	Exon 10 of 14	1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes

AF:

0.00694

AC:

1056

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00312

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.00731

AC:

1839

AN:

251474

AF XY:

0.00753

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00963

Gnomad ASJ exome

AF:

0.00714

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.0117

GnomAD4 exome

AF:

0.00948

AC:

13862

AN:

1461744

Hom.:

Cov.:

AF XY:

0.00929

AC XY:

6754

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

33480

American (AMR)

AF:

0.0106

AC:

473

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00700

AC:

183

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00396

AC:

342

AN:

86258

European-Finnish (FIN)

AF:

0.00163

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0109

AC:

12072

AN:

1111874

Other (OTH)

AF:

0.00959

AC:

579

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

668

1335

2003

2670

3338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.00694

AC:

1057

AN:

152208

Hom.:

Cov.:

AF XY:

0.00629

AC XY:

468

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41530

American (AMR)

AF:

0.0124

AC:

189

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00312

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0105

AC:

715

AN:

68014

Other (OTH)

AF:

0.0142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

102

153

204

255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00889

Hom.:

Bravo

AF:

0.00819

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.00723

AC:

878

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0132

EpiControl

AF:

0.0130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 4

Benign:2

May 29, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oculocutaneous albinism

Uncertain:1

Dec 21, 2016

Genetics - Synnovis, NHS South East Genomic Laboratory Hub

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant may be associated with cardiomyopthy. There 3 individuals present in the ExAC database that are homozygous for this variant. Insufficient evidence to move out of uncertain significance classification. -

Hermansky-Pudlak syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr251Ser in exon 10 of HPS4: This variant is not expected to have clinical sign ificance because it has been identified in 1.1% (94/8600) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs34962745). -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.15

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.19

T;.;T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.51

.;T;T;T

MetaRNN

Benign

0.0051

T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

2.0

M;.;M;.

PhyloP100

4.6

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.0

N;N;N;N

REVEL

Benign

0.060

Sift

Benign

0.26

T;T;T;T

Sift4G

Benign

0.23

T;T;T;.

Polyphen

0.15

B;B;B;.

Vest4

0.19

MutPred

0.17

Gain of disorder (P = 0.0551);.;Gain of disorder (P = 0.0551);.;

MVP

0.93

MPC

0.052

ClinPred

0.019

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.070

gMVP

0.39

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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