chr5-78110280-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003664.5(AP3B1):c.2324T>A(p.Ile775Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,609,122 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I775T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0067 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 5 hom. )

Consequence

AP3B1
NM_003664.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.744

Publications

2 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=0.002162218).

BP6

Variant 5-78110280-A-T is Benign according to our data. Variant chr5-78110280-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 354230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0067 (1020/152316) while in subpopulation AFR AF = 0.0233 (967/41570). AF 95% confidence interval is 0.022. There are 10 homozygotes in GnomAd4. There are 478 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3B1	NM_003664.5 link	c.2324T>A	p.Ile775Lys	missense_variant	Exon 20 of 27	ENST00000255194.11	NP_003655.3	O00203-1A0A0S2Z5J4
AP3B1	NM_001271769.2 link	c.2177T>A	p.Ile726Lys	missense_variant	Exon 20 of 27		NP_001258698.1	O00203-3A0A0S2Z5J4
AP3B1	NM_001410752.1 link	c.2324T>A	p.Ile775Lys	missense_variant	Exon 20 of 23		NP_001397681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11 link	c.2324T>A	p.Ile775Lys	missense_variant	Exon 20 of 27	1	NM_003664.5	ENSP00000255194.7		O00203-1

Frequencies

GnomAD3 genomes

AF:

0.00671

AC:

1022

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00175

AC:

427

AN:

243744

AF XY:

0.00128

show subpopulations

Gnomad AFR exome

AF:

0.0251

Gnomad AMR exome

AF:

0.000734

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000918

Gnomad OTH exome

AF:

0.000835

GnomAD4 exome

AF:

0.000624

AC:

909

AN:

1456806

Hom.:

Cov.:

AF XY:

0.000529

AC XY:

383

AN XY:

724352

show subpopulations

African (AFR)

AF:

0.0237

AC:

793

AN:

33420

American (AMR)

AF:

0.000787

AC:

AN:

44450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25990

East Asian (EAS)

AF:

0.00

AC:

AN:

39586

South Asian (SAS)

AF:

0.00

AC:

AN:

85552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1108850

Other (OTH)

AF:

0.00125

AC:

AN:

60158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00670

AC:

1020

AN:

152316

Hom.:

Cov.:

AF XY:

0.00642

AC XY:

478

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0233

AC:

967

AN:

41570

American (AMR)

AF:

0.00274

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68008

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

106

158

211

264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00183

Hom.:

Bravo

AF:

0.00716

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00231

AC:

281

Asia WGS

AF:

0.000578

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ile775Lys in exon 20 of AP3B1: This variant is not expected to have clinical sig nificance because it has been identified in 2.3% (103/4400) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs62001050). -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome 2

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autoinflammatory syndrome

Benign:1

Dec 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.16

CADD

Benign

3.9

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Uncertain

0.051

MutationAssessor

Benign

1.4

L;.

PhyloP100

0.74

PrimateAI

Benign

0.25

PROVEAN

Benign

0.44

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.90

T;T

Sift4G

Benign

0.95

T;T

Polyphen

0.0030

B;.

Vest4

0.22

MVP

0.38

MPC

0.13

ClinPred

0.0019

GERP RS

-1.9

Varity_R

0.035

gMVP

0.089

Mutation Taster

=99/1

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