chr22-26470757-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_022081.6(HPS4):c.558G>A(p.Ser186Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 1,614,016 control chromosomes in the GnomAD database, including 1,401 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S186S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.035 ( 105 hom., cov: 33)

Exomes 𝑓: 0.039 ( 1296 hom. )

Consequence

HPS4
NM_022081.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -4.59

Publications

6 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 22-26470757-C-T is Benign according to our data. Variant chr22-26470757-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.59 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0353 (5367/152222) while in subpopulation NFE AF = 0.0411 (2795/67998). AF 95% confidence interval is 0.0398. There are 105 homozygotes in GnomAd4. There are 2525 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 105 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6 link	c.558G>A	p.Ser186Ser	synonymous_variant	Exon 7 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.558G>A	p.Ser186Ser	synonymous_variant	Exon 7 of 14	1	NM_022081.6	ENSP00000381213.2		Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.0353

AC:

5362

AN:

152104

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0281

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0382

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0240

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0411

Gnomad OTH

AF:

0.0382

GnomAD2 exomes

AF:

0.0325

AC:

8157

AN:

251304

AF XY:

0.0326

show subpopulations

Gnomad AFR exome

AF:

0.0261

Gnomad AMR exome

AF:

0.0215

Gnomad ASJ exome

AF:

0.103

Gnomad EAS exome

AF:

0.000924

Gnomad FIN exome

AF:

0.0229

Gnomad NFE exome

AF:

0.0401

Gnomad OTH exome

AF:

0.0347

GnomAD4 exome

AF:

0.0391

AC:

57218

AN:

1461794

Hom.:

1296

Cov.:

AF XY:

0.0385

AC XY:

28022

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0266

AC:

890

AN:

33478

American (AMR)

AF:

0.0234

AC:

1048

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

2741

AN:

26132

East Asian (EAS)

AF:

0.000730

AC:

AN:

39700

South Asian (SAS)

AF:

0.0216

AC:

1864

AN:

86254

European-Finnish (FIN)

AF:

0.0241

AC:

1285

AN:

53406

Middle Eastern (MID)

AF:

0.0238

AC:

137

AN:

5758

European-Non Finnish (NFE)

AF:

0.0422

AC:

46885

AN:

1111960

Other (OTH)

AF:

0.0387

AC:

2339

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3122

6244

9366

12488

15610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1784

3568

5352

7136

8920

<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:

0.0353

AC:

5367

AN:

152222

Hom.:

105

Cov.:

AF XY:

0.0339

AC XY:

2525

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0280

AC:

1163

AN:

41536

American (AMR)

AF:

0.0382

AC:

584

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

347

AN:

3468

East Asian (EAS)

AF:

0.00154

AC:

AN:

5184

South Asian (SAS)

AF:

0.0220

AC:

106

AN:

4822

European-Finnish (FIN)

AF:

0.0240

AC:

254

AN:

10604

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0411

AC:

2795

AN:

67998

Other (OTH)

AF:

0.0388

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

272

545

817

1090

1362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0367

Hom.:

157

Bravo

AF:

0.0358

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 22, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ser186Ser in exon 7 of HPS4: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 4.3% (367/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs13054747). -

PreventionGenetics, part of Exact Sciences

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

1.3

(source)

DANN

Benign

0.85

PhyloP100

-4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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