rs141102178

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_003664.5(AP3B1):c.2188C>T(p.Arg730Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,613,826 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. R730Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

AP3B1
NM_003664.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6B:1

Conservation

PhyloP100: 0.525

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

AP3B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013520837).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000303 (46/151964) while in subpopulation NFE AF = 0.000471 (32/68000). AF 95% confidence interval is 0.000342. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3B1	NM_003664.5 link	c.2188C>T	p.Arg730Trp	missense_variant	Exon 19 of 27	ENST00000255194.11	NP_003655.3	O00203-1A0A0S2Z5J4
AP3B1	NM_001271769.2 link	c.2041C>T	p.Arg681Trp	missense_variant	Exon 19 of 27		NP_001258698.1	O00203-3A0A0S2Z5J4
AP3B1	NM_001410752.1 link	c.2188C>T	p.Arg730Trp	missense_variant	Exon 19 of 23		NP_001397681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11 link	c.2188C>T	p.Arg730Trp	missense_variant	Exon 19 of 27	1	NM_003664.5	ENSP00000255194.7		O00203-1

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000852

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000473

AC:

119

AN:

251442

AF XY:

0.000434

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.000659

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000389

AC:

568

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000360

AC XY:

262

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000403

AC:

448

AN:

1112008

Other (OTH)

AF:

0.000430

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000303

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41352

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.000852

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000471

AC:

AN:

68000

Other (OTH)

AF:

0.000959

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000562

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000568

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 2

Uncertain:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 730 of the AP3B1 protein (p.Arg730Trp). This variant is present in population databases (rs141102178, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a mild platelet defect (PMID: 32935436). ClinVar contains an entry for this variant (Variation ID: 354231). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 31, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jan 14, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: AP3B1 c.2188C>T (p.Arg730Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251442 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AP3B1 causing Hermansky-Pudlak Syndrome (0.00047 vs 0.0005), allowing no conclusion about variant significance. c.2188C>T has been reported in the literature in individuals affected with mild platelet disorder (Almazni_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hermansky-Pudlak Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32935436). ClinVar contains an entry for this variant (Variation ID: 354231). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Dec 10, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with an inherited bleeding disorder, but additional clinical information, familial segregation, and functional studies were not available (Almazani et al., 2020); This variant is associated with the following publications: (PMID: 32935436) -

Thrombocytopenia;C1458140:Abnormal bleeding

Uncertain:1

May 01, 2020

Birmingham Platelet Group; University of Birmingham

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

AP3B1-related disorder

Benign:1

Jun 02, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.42

T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.85

T;D

M_CAP

Benign

0.084

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.

PhyloP100

0.53

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.059

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

0.48

P;.

Vest4

0.10

MVP

0.31

MPC

0.12

ClinPred

0.019

GERP RS

2.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.041

gMVP

0.091

Mutation Taster

=95/5

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over