15-90998965-G-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_018668.5(VPS33B):c.*10C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,461,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000028 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
VPS33B
NM_018668.5 3_prime_UTR
NM_018668.5 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.15
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 Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| VPS33B | NM_018668.5 | c.*10C>T | 3_prime_UTR_variant | 23/23 | ENST00000333371.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| VPS33B | ENST00000333371.8 | c.*10C>T | 3_prime_UTR_variant | 23/23 | 1 | NM_018668.5 | P1 | ||
| VPS33B | ENST00000535906.1 | c.*10C>T | 3_prime_UTR_variant | 22/22 | 2 | ||||
| VPS33B | ENST00000557470.5 | n.237C>T | non_coding_transcript_exon_variant | 3/3 | 5 | ||||
| VPS33B | ENST00000574755.5 | c.*1559C>T | 3_prime_UTR_variant, NMD_transcript_variant | 22/22 | 2 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 152160Hom.: 0 Cov.: 32 FAILED QC
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251042Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135668
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GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461628Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 19AN XY: 727094
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GnomAD4 genome 0.00 AC: 0AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74324
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Arthrogryposis, renal dysfunction, and cholestasis 1 Uncertain:1
| Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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