chr22-26457915-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_022081.6(HPS4):c.1899C>T(p.Val633Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,614,188 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 53 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 39 hom. )

Consequence

HPS4
NM_022081.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.628

Publications

2 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 22-26457915-G-A is Benign according to our data. Variant chr22-26457915-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.628 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2177/152362) while in subpopulation AFR AF = 0.0493 (2051/41580). AF 95% confidence interval is 0.0475. There are 53 homozygotes in GnomAd4. There are 957 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6 link	c.1899C>T	p.Val633Val	synonymous_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.1899C>T	p.Val633Val	synonymous_variant	Exon 13 of 14	1	NM_022081.6	ENSP00000381213.2		Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2177

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0494

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00667

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.00382

AC:

959

AN:

251230

AF XY:

0.00283

show subpopulations

Gnomad AFR exome

AF:

0.0524

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00144

AC:

2104

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

909

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0504

AC:

1689

AN:

33480

American (AMR)

AF:

0.00286

AC:

128

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

1112008

Other (OTH)

AF:

0.00343

AC:

207

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

124

248

372

496

620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.0143

AC:

2177

AN:

152362

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

957

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0493

AC:

2051

AN:

41580

American (AMR)

AF:

0.00666

AC:

102

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68042

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

112

224

335

447

559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00679

Hom.:

Bravo

AF:

0.0169

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

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

Nov 24, 2020

GeneDx

Significance: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

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Val633Val in exon 13 of HPS4: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 5.2% (230/4406) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs35993959). -

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

-0.38

CADD

Benign

9.5

(source)

DANN

Benign

0.79

PhyloP100

0.63

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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