rs121908906
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003664.5(AP3B1):c.1525C>T(p.Arg509*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
AP3B1
NM_003664.5 stop_gained
NM_003664.5 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.98
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 Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-78141268-G-A is Pathogenic according to our data. Variant chr5-78141268-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6377.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-78141268-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AP3B1 | NM_003664.5 | c.1525C>T | p.Arg509* | stop_gained | 15/27 | ENST00000255194.11 | NP_003655.3 | |
AP3B1 | NM_001271769.2 | c.1378C>T | p.Arg460* | stop_gained | 15/27 | NP_001258698.1 | ||
AP3B1 | NM_001410752.1 | c.1525C>T | p.Arg509* | stop_gained | 15/23 | NP_001397681.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AP3B1 | ENST00000255194.11 | c.1525C>T | p.Arg509* | stop_gained | 15/27 | 1 | NM_003664.5 | ENSP00000255194.7 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461370Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727010
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31
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hermansky-Pudlak syndrome 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 09, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg509*) in the AP3B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP3B1 are known to be pathogenic (PMID: 16507770, 23403622). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 11809908). This variant is also known as C1578T. ClinVar contains an entry for this variant (Variation ID: 6377). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2002 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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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