rs746205404
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_003664.5(AP3B1):c.2779G>A(p.Gly927Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000165 in 1,453,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
AP3B1
NM_003664.5 missense
NM_003664.5 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 5.28
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000165 (24/1453320) while in subpopulation EAS AF= 0.000555 (22/39622). AF 95% confidence interval is 0.000376. There are 0 homozygotes in gnomad4_exome. There are 13 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AP3B1 | NM_003664.5 | c.2779G>A | p.Gly927Ser | missense_variant | 23/27 | ENST00000255194.11 | NP_003655.3 | |
AP3B1 | NM_001271769.2 | c.2632G>A | p.Gly878Ser | missense_variant | 23/27 | NP_001258698.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AP3B1 | ENST00000255194.11 | c.2779G>A | p.Gly927Ser | missense_variant | 23/27 | 1 | NM_003664.5 | ENSP00000255194.7 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000719 AC: 18AN: 250352Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135342
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GnomAD4 exome AF: 0.0000165 AC: 24AN: 1453320Hom.: 0 Cov.: 30 AF XY: 0.0000180 AC XY: 13AN XY: 723392
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2022 | The c.2779G>A (p.G927S) alteration is located in exon 23 (coding exon 23) of the AP3B1 gene. This alteration results from a G to A substitution at nucleotide position 2779, causing the glycine (G) at amino acid position 927 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hermansky-Pudlak syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 24, 2021 | This sequence change replaces glycine with serine at codon 927 of the AP3B1 protein (p.Gly927Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with AP3B1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Uncertain
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Benign
Sift
Pathogenic
D;D
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MutPred
Gain of catalytic residue at G927 (P = 0.0766);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at