rs3213583

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.707-28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.887 in 1,582,382 control chromosomes in the GnomAD database, including 625,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.84 ( 54152 hom., cov: 31)

Exomes 𝑓: 0.89 ( 571512 hom. )

Consequence

HPS4
NM_022081.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.491

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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 22-26465579-A-G is Benign according to our data. Variant chr22-26465579-A-G is described in ClinVar as Benign. ClinVar VariationId is 261538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022081.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HPS4	NM_022081.6	MANE Select	c.707-28T>C	intron	N/A	NP_071364.4
HPS4	NM_001349900.2		c.761-28T>C	intron	N/A	NP_001336829.1	F1LLU8
HPS4	NM_001349901.1		c.761-28T>C	intron	N/A	NP_001336830.1	F1LLU8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HPS4	ENST00000398145.7	TSL:1 MANE Select	c.707-28T>C	intron	N/A	ENSP00000381213.2	Q9NQG7-1
HPS4	ENST00000402105.7	TSL:1	c.692-28T>C	intron	N/A	ENSP00000384185.3	Q9NQG7-3
HPS4	ENST00000439453.5	TSL:1	n.*225-28T>C	intron	N/A	ENSP00000406764.1	F8WC53

Frequencies

GnomAD3 genomes

AF:

0.839

AC:

127486

AN:

152012

Hom.:

54141

Cov.:

show subpopulations

Gnomad AFR

AF:

0.709

Gnomad AMI

AF:

0.832

Gnomad AMR

AF:

0.758

Gnomad ASJ

AF:

0.877

Gnomad EAS

AF:

0.851

Gnomad SAS

AF:

0.903

Gnomad FIN

AF:

0.965

Gnomad MID

AF:

0.908

Gnomad NFE

AF:

0.908

Gnomad OTH

AF:

0.853

GnomAD2 exomes

AF:

0.861

AC:

215418

AN:

250248

AF XY:

0.873

show subpopulations

Gnomad AFR exome

AF:

0.705

Gnomad AMR exome

AF:

0.673

Gnomad ASJ exome

AF:

0.877

Gnomad EAS exome

AF:

0.854

Gnomad FIN exome

AF:

0.964

Gnomad NFE exome

AF:

0.907

Gnomad OTH exome

AF:

0.882

GnomAD4 exome

AF:

0.892

AC:

1276076

AN:

1430252

Hom.:

571512

Cov.:

AF XY:

0.895

AC XY:

638781

AN XY:

713764

show subpopulations

African (AFR)

AF:

0.704

AC:

23068

AN:

32788

American (AMR)

AF:

0.687

AC:

30675

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.874

AC:

22668

AN:

25944

East Asian (EAS)

AF:

0.849

AC:

33521

AN:

39482

South Asian (SAS)

AF:

0.913

AC:

78145

AN:

85586

European-Finnish (FIN)

AF:

0.959

AC:

50526

AN:

52672

Middle Eastern (MID)

AF:

0.907

AC:

5159

AN:

5686

European-Non Finnish (NFE)

AF:

0.904

AC:

979786

AN:

1084034

Other (OTH)

AF:

0.884

AC:

52528

AN:

59394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

6524

13049

19573

26098

32622

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20644

41288

61932

82576

103220

<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:

0.838

AC:

127548

AN:

152130

Hom.:

54152

Cov.:

AF XY:

0.839

AC XY:

62435

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.709

AC:

29379

AN:

41454

American (AMR)

AF:

0.758

AC:

11573

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.877

AC:

3046

AN:

3472

East Asian (EAS)

AF:

0.851

AC:

4384

AN:

5154

South Asian (SAS)

AF:

0.903

AC:

4361

AN:

4828

European-Finnish (FIN)

AF:

0.965

AC:

10233

AN:

10606

Middle Eastern (MID)

AF:

0.905

AC:

266

AN:

294

European-Non Finnish (NFE)

AF:

0.908

AC:

61755

AN:

68028

Other (OTH)

AF:

0.849

AC:

1794

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

990

1981

2971

3962

4952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

886

1772

2658

3544

4430

<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:

0.875

Hom.:

11204

Bravo

AF:

0.815

Asia WGS

AF:

0.844

AC:

2936

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hermansky-Pudlak syndrome 4 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

0.49

BranchPoint Hunter

3.0

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)

0.0

Details are displayed if max score is > 0.2

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

Publications

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over