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.

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
AP3B1	NM_003664.5	MANE Select	c.1754T>A	p.Val585Glu	missense	Exon 16 of 27	NP_003655.3
AP3B1	NM_001271769.2		c.1607T>A	p.Val536Glu	missense	Exon 16 of 27	NP_001258698.1
AP3B1	NM_001410752.1		c.1754T>A	p.Val585Glu	missense	Exon 16 of 23	NP_001397681.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.1754T>A	p.Val585Glu	missense	Exon 16 of 27	ENSP00000255194.7
AP3B1	ENST00000519295.7	TSL:1	c.1607T>A	p.Val536Glu	missense	Exon 16 of 27	ENSP00000430597.1
AP3B1	ENST00000913629.1		c.1754T>A	p.Val585Glu	missense	Exon 16 of 27	ENSP00000583688.1

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

ALSPAC

AF:

0.938

AC:

3616

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Hermansky-Pudlak syndrome 2 (2)

not provided (3)

Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.38

MetaRNN

Benign

0.000019

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

PhyloP100

6.3

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

4.7

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.090

MPC

0.061

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over