rs146871001

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP3_ModerateBP6BS1BS2

The NM_003664.5(AP3B1):c.942G>A(p.Ala314=) 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:1B:3

Conservation

PhyloP100: 0.530

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP3

Splicing scoreres supports a deletorius 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 id is 354245.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr5-78181507-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AP3B1	NM_003664.5 linkuse as main transcript	c.942G>A	p.Ala314=	splice_region_variant, synonymous_variant	8/27	ENST00000255194.11
AP3B1	NM_001271769.2 linkuse as main transcript	c.795G>A	p.Ala265=	splice_region_variant, synonymous_variant	8/27
AP3B1	NM_001410752.1 linkuse as main transcript	c.942G>A	p.Ala314=	splice_region_variant, synonymous_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP3B1	ENST00000255194.11 linkuse as main transcript	c.942G>A	p.Ala314=	splice_region_variant, synonymous_variant	8/27	1	NM_003664.5	P2	O00203-1

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

GnomAD3 exomes

AF:

0.00189

AC:

472

AN:

250310

Hom.:

AF XY:

0.00154

AC XY:

209

AN XY:

135318

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 SAS exome

AF:

0.000262

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

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00933

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00647

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.000418

Gnomad4 NFE exome

AF:

0.0000891

Gnomad4 OTH exome

AF:

0.000796

GnomAD4 genome

AF:

0.00108

AC:

165

AN:

152188

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00563

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00732

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000177

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000506

Hom.:

Bravo

AF:

0.00156

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 2

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2019

Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Oct 20, 2023

Variant summary: AP3B1 c.942G>A (p.Ala314Ala) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the 5' canonical splicing donor site. One predict the variant weakens the 5' canonical splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0019 in 250310 control chromosomes, predominantly at a frequency of 0.0097 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in AP3B1 causing Hermansky-Pudlak Syndrome phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.942G>A in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over