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rs146871001

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS1

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. 2/2 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

2
Splicing: ADA: 0.9998
2

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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. 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: {Uncertain_significance=1, Likely_benign=3}. 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. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AP3B1NM_003664.5 linkuse as main transcriptc.942G>A p.Ala314= splice_region_variant, synonymous_variant 8/27 ENST00000255194.11
AP3B1NM_001271769.2 linkuse as main transcriptc.795G>A p.Ala265= splice_region_variant, synonymous_variant 8/27
AP3B1NM_001410752.1 linkuse as main transcriptc.942G>A p.Ala314= splice_region_variant, synonymous_variant 8/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AP3B1ENST00000255194.11 linkuse as main transcriptc.942G>A p.Ala314= splice_region_variant, synonymous_variant 8/271 NM_003664.5 P2O00203-1

Frequencies

GnomAD3 genomes
AF:
0.00110
AC:
167
AN:
152070
Hom.:
1
Cov.:
32
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.:
1
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.:
6
Cov.:
31
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.:
1
Cov.:
32
AF XY:
0.00128
AC XY:
95
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.:
0
Bravo
AF:
0.00156
Asia WGS
AF:
0.00606
AC:
21
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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 submitterclinical testingInvitaeJan 28, 2024- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 10, 2019Has 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 20, 2023Variant 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
21
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.

Other links and lift over

dbSNP: rs146871001; hg19: chr5-77477331; COSMIC: COSV54892575; API