rs141832130

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3BS1BS2

The NM_003664.5(AP3B1):c.1022G>A(p.Arg341His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 1,613,062 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R341C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 3 hom. )

Consequence

AP3B1
NM_003664.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 7.57

Publications

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

AP3B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.789

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00023 (35/152120) while in subpopulation NFE AF = 0.000324 (22/68002). AF 95% confidence interval is 0.000218. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003664.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP3B1	NM_003664.5	MANE Select	c.1022G>A	p.Arg341His	missense	Exon 9 of 27	NP_003655.3
AP3B1	NM_001271769.2		c.875G>A	p.Arg292His	missense	Exon 9 of 27	NP_001258698.1	O00203-3
AP3B1	NM_001410752.1		c.1022G>A	p.Arg341His	missense	Exon 9 of 23	NP_001397681.1	A0A8Q3SIM7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.1022G>A	p.Arg341His	missense	Exon 9 of 27	ENSP00000255194.7	O00203-1
AP3B1	ENST00000519295.7	TSL:1	c.875G>A	p.Arg292His	missense	Exon 9 of 27	ENSP00000430597.1	O00203-3
AP3B1	ENST00000913629.1		c.1022G>A	p.Arg341His	missense	Exon 9 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000223

AC:

AN:

251320

AF XY:

0.000206

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000490

AC:

716

AN:

1460942

Hom.:

Cov.:

AF XY:

0.000466

AC XY:

339

AN XY:

726808

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33464

American (AMR)

AF:

0.000246

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000602

AC:

669

AN:

1111208

Other (OTH)

AF:

0.000497

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.000230

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41488

American (AMR)

AF:

0.000197

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000324

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000413

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000272

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hermansky-Pudlak syndrome 2 (3)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.41

MutationAssessor

Pathogenic

3.3

PhyloP100

7.6

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.66

Sift

Uncertain

0.014

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.87

MVP

0.70

MPC

0.19

ClinPred

0.81

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.55

Mutation Taster

=43/57

disease causing

(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