rs139344924

Variant names:

Variant summary

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

The NM_003664.5(AP3B1):c.2661C>A(p.Phe887Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,614,086 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 ( 5 hom., cov: 32)

Exomes 𝑓: 0.011 ( 105 hom. )

Consequence

AP3B1
NM_003664.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 2.63

Publications

12 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0114659965).

BP6

Variant 5-78039191-G-T is Benign according to our data. Variant chr5-78039191-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210189.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00694 (1056/152260) while in subpopulation SAS AF = 0.0137 (66/4828). AF 95% confidence interval is 0.0111. There are 5 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3B1	NM_003664.5 link	c.2661C>A	p.Phe887Leu	missense_variant	Exon 23 of 27	ENST00000255194.11	NP_003655.3	O00203-1A0A0S2Z5J4
AP3B1	NM_001271769.2 link	c.2514C>A	p.Phe838Leu	missense_variant	Exon 23 of 27		NP_001258698.1	O00203-3A0A0S2Z5J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11 link	c.2661C>A	p.Phe887Leu	missense_variant	Exon 23 of 27	1	NM_003664.5	ENSP00000255194.7		O00203-1

Frequencies

GnomAD3 genomes

AF:

0.00694

AC:

1056

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00774

AC:

1947

AN:

251458

AF XY:

0.00819

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00338

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00259

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.00912

GnomAD4 exome

AF:

0.0105

AC:

15376

AN:

1461826

Hom.:

105

Cov.:

AF XY:

0.0105

AC XY:

7618

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

33480

American (AMR)

AF:

0.00369

AC:

165

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00126

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.0128

AC:

1100

AN:

86258

European-Finnish (FIN)

AF:

0.00307

AC:

164

AN:

53416

Middle Eastern (MID)

AF:

0.00919

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0117

AC:

13054

AN:

1111972

Other (OTH)

AF:

0.0125

AC:

757

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

820

1641

2461

3282

4102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00694

AC:

1056

AN:

152260

Hom.:

Cov.:

AF XY:

0.00647

AC XY:

482

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

41570

American (AMR)

AF:

0.00412

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0137

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0117

AC:

798

AN:

68002

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00945

Hom.:

Bravo

AF:

0.00636

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.00784

AC:

952

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.00865

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 28, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely 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

Phe887Leu in exon 23 of AP3B1: This variant is not expected to have clinical sig nificance because it has been identified in 1.2% (99/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs139344924). -

Hermansky-Pudlak syndrome 2

Benign:2

Mar 20, 2019

Johns Hopkins Genomics, Johns Hopkins University

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

- -

not provided

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AP3B1: BP4, BS1, BS2 -

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

- -

Autoinflammatory syndrome

Benign:1

Feb 05, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

0.30

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.063

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.

PhyloP100

2.6

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.059

Sift

Benign

0.65

T;T

Sift4G

Benign

0.65

T;T

Polyphen

0.0010

B;.

Vest4

0.35

MutPred

0.37

Gain of sheet (P = 0.0827);.;

MVP

0.28

MPC

0.068

ClinPred

0.013

GERP RS

5.8

PromoterAI

-0.036

Neutral

(source)

Varity_R

0.10

gMVP

0.58

Mutation Taster

=93/7

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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rs139344924

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