rs139344924

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=5}. Variant chr5-78039191-G-T is described in Lovd as [Likely_benign]. Variant chr5-78039191-G-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP3B1	NM_003664.5 linkuse as main transcript	c.2661C>A	p.Phe887Leu	missense_variant	23/27	ENST00000255194.11
AP3B1	NM_001271769.2 linkuse as main transcript	c.2514C>A	p.Phe838Leu	missense_variant	23/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP3B1	ENST00000255194.11 linkuse as main transcript	c.2661C>A	p.Phe887Leu	missense_variant	23/27	1	NM_003664.5	P2	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

GnomAD3 exomes

AF:

0.00774

AC:

1947

AN:

251458

Hom.:

AF XY:

0.00819

AC XY:

1113

AN XY:

135904

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 SAS exome

AF:

0.0129

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

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.00369

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0128

Gnomad4 FIN exome

AF:

0.00307

Gnomad4 NFE exome

AF:

0.0117

Gnomad4 OTH exome

AF:

0.0125

GnomAD4 genome

AF:

0.00694

AC:

1056

AN:

152260

Hom.:

Cov.:

AF XY:

0.00647

AC XY:

482

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.00412

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0137

Gnomad4 FIN

AF:

0.00264

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00982

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

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hermansky-Pudlak syndrome 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	AP3B1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hermansky-Pudlak syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 05, 2021

- -

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

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;.

MutationTaster

Benign

0.89

D;D

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

Varity_R

0.10

gMVP

0.58

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over