rs16945153
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1
The NM_018668.5(VPS33B):c.1656A>T(p.Thr552=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0102 in 1,614,110 control chromosomes in the GnomAD database, including 1,400 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 Benign (★★).
Frequency
Genomes: 𝑓 0.053 ( 713 hom., cov: 32)
Exomes 𝑓: 0.0058 ( 687 hom. )
Consequence
VPS33B
NM_018668.5 splice_region, synonymous
NM_018668.5 splice_region, synonymous
Scores
2
Splicing: ADA: 0.9942
2
Clinical Significance
Conservation
PhyloP100: 3.65
Genes affected
VPS33B (HGNC:12712): (VPS33B late endosome and lysosome associated) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene is a member of the Sec-1 domain family, and encodes the human ortholog of rat Vps33b which is homologous to the yeast class C Vps33 protein. The mammalian class C vacuolar protein sorting proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Mutations in this gene are associated with arthrogryposis-renal dysfunction-cholestasis syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -15 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BP6
?
Variant 15-90999901-T-A is Benign according to our data. Variant chr15-90999901-T-A is described in ClinVar as [Benign]. Clinvar id is 261042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS33B | NM_018668.5 | c.1656A>T | p.Thr552= | splice_region_variant, synonymous_variant | 21/23 | ENST00000333371.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS33B | ENST00000333371.8 | c.1656A>T | p.Thr552= | splice_region_variant, synonymous_variant | 21/23 | 1 | NM_018668.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0528 AC: 8032AN: 152112Hom.: 708 Cov.: 32
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GnomAD3 exomes AF: 0.0144 AC: 3609AN: 251472Hom.: 312 AF XY: 0.0105 AC XY: 1432AN XY: 135910
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GnomAD4 exome AF: 0.00578 AC: 8444AN: 1461880Hom.: 687 Cov.: 32 AF XY: 0.00508 AC XY: 3696AN XY: 727240
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GnomAD4 genome ? AF: 0.0530 AC: 8067AN: 152230Hom.: 713 Cov.: 32 AF XY: 0.0523 AC XY: 3894AN XY: 74448
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ClinVar
Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Arthrogryposis, renal dysfunction, and cholestasis 1 Benign:1
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at