5-78129204-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003664.5(AP3B1):c.1754T>A(p.Val585Glu) variant causes a missense change. The variant allele was found at a frequency of 0.906 in 1,613,158 control chromosomes in the GnomAD database, including 668,093 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V585A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.91 ( 63548 hom., cov: 31)

Exomes 𝑓: 0.91 ( 604545 hom. )

Consequence

AP3B1
NM_003664.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 6.29

Publications

43 publications found

Variant links:

Genes affected

AP3B1 (HGNC:566): (adaptor related protein complex 3 subunit beta 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is part of the heterotetrameric AP-3 protein complex which interacts with the scaffolding protein clathrin. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2012]

AP3B1 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P

AP3B1 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=1.8920544E-5).

BP6

Variant 5-78129204-A-T is Benign according to our data. Variant chr5-78129204-A-T is described in ClinVar as Benign. ClinVar VariationId is 162753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AP3B1	NM_003664.5 link	c.1754T>A	p.Val585Glu	missense_variant	Exon 16 of 27	ENST00000255194.11	NP_003655.3
AP3B1	NM_001271769.2 link	c.1607T>A	p.Val536Glu	missense_variant	Exon 16 of 27		NP_001258698.1
AP3B1	NM_001410752.1 link	c.1754T>A	p.Val585Glu	missense_variant	Exon 16 of 23		NP_001397681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11 link	c.1754T>A	p.Val585Glu	missense_variant	Exon 16 of 27	1	NM_003664.5	ENSP00000255194.7

Frequencies

GnomAD3 genomes

AF:

0.909

AC:

138144

AN:

151986

Hom.:

63498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.953

Gnomad AMI

AF:

0.960

Gnomad AMR

AF:

0.894

Gnomad ASJ

AF:

0.909

Gnomad EAS

AF:

0.453

Gnomad SAS

AF:

0.783

Gnomad FIN

AF:

0.894

Gnomad MID

AF:

0.886

Gnomad NFE

AF:

0.931

Gnomad OTH

AF:

0.905

GnomAD2 exomes

AF:

0.861

AC:

216280

AN:

251168

AF XY:

0.862

show subpopulations

Gnomad AFR exome

AF:

0.955

Gnomad AMR exome

AF:

0.848

Gnomad ASJ exome

AF:

0.908

Gnomad EAS exome

AF:

0.428

Gnomad FIN exome

AF:

0.892

Gnomad NFE exome

AF:

0.927

Gnomad OTH exome

AF:

0.888

GnomAD4 exome

AF:

0.906

AC:

1323071

AN:

1461054

Hom.:

604545

Cov.:

AF XY:

0.903

AC XY:

656180

AN XY:

726862

show subpopulations

African (AFR)

AF:

0.957

AC:

32032

AN:

33462

American (AMR)

AF:

0.859

AC:

38379

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.910

AC:

23774

AN:

26122

East Asian (EAS)

AF:

0.464

AC:

18393

AN:

39640

South Asian (SAS)

AF:

0.803

AC:

69248

AN:

86234

European-Finnish (FIN)

AF:

0.891

AC:

47564

AN:

53402

Middle Eastern (MID)

AF:

0.866

AC:

4984

AN:

5758

European-Non Finnish (NFE)

AF:

0.931

AC:

1034985

AN:

1111388

Other (OTH)

AF:

0.890

AC:

53712

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

6345

12690

19036

25381

31726

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21442

42884

64326

85768

107210

<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:

0.909

AC:

138251

AN:

152104

Hom.:

63548

Cov.:

AF XY:

0.902

AC XY:

67087

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.953

AC:

39570

AN:

41530

American (AMR)

AF:

0.894

AC:

13647

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.909

AC:

3155

AN:

3472

East Asian (EAS)

AF:

0.453

AC:

2337

AN:

5162

South Asian (SAS)

AF:

0.782

AC:

3769

AN:

4822

European-Finnish (FIN)

AF:

0.894

AC:

9469

AN:

10590

Middle Eastern (MID)

AF:

0.888

AC:

261

AN:

294

European-Non Finnish (NFE)

AF:

0.931

AC:

63262

AN:

67944

Other (OTH)

AF:

0.904

AC:

1909

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

567

1134

1701

2268

2835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

896

1792

2688

3584

4480

<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:

0.924

Hom.:

16608

Bravo

AF:

0.908

TwinsUK

AF:

0.923

AC:

3422

ESP6500AA

AF:

0.950

AC:

4187

ESP6500EA

AF:

0.924

AC:

7945

ExAC

AF:

0.863

AC:

104731

EpiCase

AF:

0.932

EpiControl

AF:

0.929

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val585Glu in exon 16 of AP3B1: This variant is not expected to have clinical sig nificance because it has been identified in 7.6% (655/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs6453373).

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >10% in Exome Aggregation Consortium.

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied by a panel of primary immunodeficiencies. Number of patients: 96. Only high quality variants are reported.

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing.

Hermansky-Pudlak syndrome 2

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.035

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.27

LIST_S2

Benign

0.38

T;T

MetaRNN

Benign

0.000019

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

N;.

PhyloP100

6.3

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

4.7

N;N

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.090

ClinPred

0.0028

GERP RS

5.4

Varity_R

0.18

gMVP

0.36

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

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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