rs146503597

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003664.5(AP3B1):c.2995G>A(p.Val999Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00685 in 1,613,418 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0050 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 61 hom. )

Consequence

AP3B1
NM_003664.5 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.42

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=0.007074684).

BP6

Variant 5-78015546-C-T is Benign according to our data. Variant chr5-78015546-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195962.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr5-78015546-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00499 (759/152166) while in subpopulation AMR AF= 0.0105 (161/15276). AF 95% confidence interval is 0.00921. There are 3 homozygotes in gnomad4. There are 357 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP3B1	NM_003664.5 linkuse as main transcript	c.2995G>A	p.Val999Met	missense_variant, splice_region_variant	26/27	ENST00000255194.11
AP3B1	NM_001271769.2 linkuse as main transcript	c.2848G>A	p.Val950Met	missense_variant, splice_region_variant	26/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP3B1	ENST00000255194.11 linkuse as main transcript	c.2995G>A	p.Val999Met	missense_variant, splice_region_variant	26/27	1	NM_003664.5	P2	O00203-1

Frequencies

GnomAD3 genomes

AF:

0.00499

AC:

759

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00312

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00716

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00413

AC:

1038

AN:

251256

Hom.:

AF XY:

0.00416

AC XY:

565

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00422

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00324

Gnomad NFE exome

AF:

0.00662

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00704

AC:

10291

AN:

1461252

Hom.:

Cov.:

AF XY:

0.00683

AC XY:

4963

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00411

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00270

Gnomad4 NFE exome

AF:

0.00850

Gnomad4 OTH exome

AF:

0.00750

GnomAD4 genome

AF:

0.00499

AC:

759

AN:

152166

Hom.:

Cov.:

AF XY:

0.00480

AC XY:

357

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.0105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00312

Gnomad4 NFE

AF:

0.00716

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00667

Hom.:

Bravo

AF:

0.00537

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.00380

AC:

462

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00753

EpiControl

AF:

0.00640

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 14, 2016	- -

Hermansky-Pudlak syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hermansky-Pudlak syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

AP3B1: BP4, BS2 -

Autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.15

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.4

N;.

MutationTaster

Benign

0.91

D;D

PrimateAI

Benign

0.34

PROVEAN

Benign

0.84

N;N

REVEL

Benign

0.072

Sift

Benign

0.33

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.0

B;.

Vest4

0.18

MVP

0.13

MPC

0.043

ClinPred

0.0065

GERP RS

-0.17

Varity_R

0.024

gMVP

0.12

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