dbSNP rs146871001: AP3B1:p.Ala314Ala (chr5-78181507-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PP3_ModerateBP6BS1BS2

The NM_003664.5(AP3B1):c.942G>A(p.Ala314Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 1,612,038 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 6 hom. )

Consequence

AP3B1
NM_003664.5 splice_region, synonymous

Scores

Splicing: ADA: 0.9998

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.530

Publications

4 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:

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ACMG classification

Classification was made for transcript

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

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant 5-78181507-C-T is Benign according to our data. Variant chr5-78181507-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 354245.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00108 (165/152188) while in subpopulation EAS AF = 0.00732 (38/5188). AF 95% confidence interval is 0.00549. There are 1 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 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.942G>A	p.Ala314Ala	splice_region synonymous	Exon 8 of 27	NP_003655.3
AP3B1	NM_001271769.2		c.795G>A	p.Ala265Ala	splice_region synonymous	Exon 8 of 27	NP_001258698.1	O00203-3
AP3B1	NM_001410752.1		c.942G>A	p.Ala314Ala	splice_region synonymous	Exon 8 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.942G>A	p.Ala314Ala	splice_region synonymous	Exon 8 of 27	ENSP00000255194.7	O00203-1
AP3B1	ENST00000519295.7	TSL:1	c.795G>A	p.Ala265Ala	splice_region synonymous	Exon 8 of 27	ENSP00000430597.1	O00203-3
AP3B1	ENST00000913629.1		c.942G>A	p.Ala314Ala	splice_region synonymous	Exon 8 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

167

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00570

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00750

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00189

AC:

472

AN:

250310

AF XY:

0.00154

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00968

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00419

Gnomad FIN exome

AF:

0.000516

Gnomad NFE exome

AF:

0.000239

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.000603

AC:

881

AN:

1459850

Hom.:

Cov.:

AF XY:

0.000587

AC XY:

426

AN XY:

726294

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33440

American (AMR)

AF:

0.00933

AC:

417

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26106

East Asian (EAS)

AF:

0.00647

AC:

256

AN:

39568

South Asian (SAS)

AF:

0.000267

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.000418

AC:

AN:

52686

Middle Eastern (MID)

AF:

0.000536

AC:

AN:

5602

European-Non Finnish (NFE)

AF:

0.0000891

AC:

AN:

1111278

Other (OTH)

AF:

0.000796

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00108

AC:

165

AN:

152188

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41558

American (AMR)

AF:

0.00563

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00732

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000177

AC:

AN:

67954

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000644

Hom.:

Bravo

AF:

0.00156

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hermansky-Pudlak syndrome 2 (3)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=41/59

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.34

Position offset: 0

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