rs1555460030

Variant names:

• chr15-91014026-TGGCCAACATGGTGAAACTCTGTCTCTACTAAAAACACAAAAAATTAGCCCGATCTGGTGGTGGGCACCTGTAATCCCAGCTACTTGGGAGGCTAAGGCAAGAGAATCGCTTGAACCCAGGAGGCGGAGGTTGCAGTGAGCCGAGATCGTGCCATTGCACTCCAGACTGGGCAACAAGAGTGAAACTCCGTCTCAAAAAAAAAAAAAAAAAAAAAAAGAAGCGGGGAAGCAGACATCCTCCACAAGTGCTACGGCCAACTCAAACAATTATTTTCTTATTAGAGGGTCCTTATGGCCAAGGCCCTTAGATTTTGCCCGCCCTTTCCCACAGTTACACATAGTACCATGGCACACTCACTGGCAATGTATCGCATATTCTTGATGCGGGGTCTGACCAAGAAGCACAATCTATGAGAGAGAAAGAAAAAAAAACAGTGAAGAAGAATTATCAAGTTGGATAGCAACTTAGAAGAAACTGAAACAATACCAACTCTTTTGCCATTTGCCCTACAGGTCTCATCCTAGCCAAAGCTATGCTATTCTCTTGGTCCACCATATACCAACCACAGAAGATACCTCTCAACACAATGGGTATAATGTGATGAGCTGGGTACATTACTGGCCCTATGGTGGACCCAAAAGTTCCTGTTCTCAAATAATTTACAATCCAGTGGGCAAAAAAAGATGCAGATATGGAGTATATTAACAATCAGTGCTGAAAAACAATATAAGAATACCCCATAAAAATATACAATTATTATCTGTCAGTTAAAAATAAAGGCTGGGCATGGTGGCTCACACCTGTAATCTTAACACTCCGGGAAGCCAAGGTGAGAAGATTGCTTGAGCTCAGGAGTTCGAAACTAGCCTCAGCAACACAGTGAGACCTCATCTCTATTAAAAATAATAATAGTGCTGTAATCCCAGCACTTTGGGAGGCAGAGGCGCGTGGATCACCTGAGGTCAGGAGTTTGAGACCAGCCCA-T
• rs1555460030
• NM_018668.5:c.240-577_290-156del

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_018668.5(VPS33B):​c.240-577_290-156del variant causes a exon loss, splice acceptor, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: VPS33B NM_018668.5 exon_loss, splice_acceptor, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.33
• Publications: 4 publications found

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]

ENSG00000284946 (HGNC:):

VPS33B-DT (HGNC:51413): (VPS33B divergent transcript)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 15-91014026-TGGCCAACATGGTGAAACTCTGTCTCTACTAAAAACACAAAAAATTAGCCCGATCTGGTGGTGGGCACCTGTAATCCCAGCTACTTGGGAGGCTAAGGCAAGAGAATCGCTTGAACCCAGGAGGCGGAGGTTGCAGTGAGCCGAGATCGTGCCATTGCACTCCAGACTGGGCAACAAGAGTGAAACTCCGTCTCAAAAAAAAAAAAAAAAAAAAAAAGAAGCGGGGAAGCAGACATCCTCCACAAGTGCTACGGCCAACTCAAACAATTATTTTCTTATTAGAGGGTCCTTATGGCCAAGGCCCTTAGATTTTGCCCGCCCTTTCCCACAGTTACACATAGTACCATGGCACACTCACTGGCAATGTATCGCATATTCTTGATGCGGGGTCTGACCAAGAAGCACAATCTATGAGAGAGAAAGAAAAAAAAACAGTGAAGAAGAATTATCAAGTTGGATAGCAACTTAGAAGAAACTGAAACAATACCAACTCTTTTGCCATTTGCCCTACAGGTCTCATCCTAGCCAAAGCTATGCTATTCTCTTGGTCCACCATATACCAACCACAGAAGATACCTCTCAACACAATGGGTATAATGTGATGAGCTGGGTACATTACTGGCCCTATGGTGGACCCAAAAGTTCCTGTTCTCAAATAATTTACAATCCAGTGGGCAAAAAAAGATGCAGATATGGAGTATATTAACAATCAGTGCTGAAAAACAATATAAGAATACCCCATAAAAATATACAATTATTATCTGTCAGTTAAAAATAAAGGCTGGGCATGGTGGCTCACACCTGTAATCTTAACACTCCGGGAAGCCAAGGTGAGAAGATTGCTTGAGCTCAGGAGTTCGAAACTAGCCTCAGCAACACAGTGAGACCTCATCTCTATTAAAAATAATAATAGTGCTGTAATCCCAGCACTTTGGGAGGCAGAGGCGCGTGGATCACCTGAGGTCAGGAGTTTGAGACCAGCCCA-T is Pathogenic according to our data. Variant chr15-91014026-TGGCCAACATGGTGAAACTCTGTCTCTACTAAAAACACAAAAAATTAGCCCGATCTGGTGGTGGGCACCTGTAATCCCAGCTACTTGGGAGGCTAAGGCAAGAGAATCGCTTGAACCCAGGAGGCGGAGGTTGCAGTGAGCCGAGATCGTGCCATTGCACTCCAGACTGGGCAACAAGAGTGAAACTCCGTCTCAAAAAAAAAAAAAAAAAAAAAAAGAAGCGGGGAAGCAGACATCCTCCACAAGTGCTACGGCCAACTCAAACAATTATTTTCTTATTAGAGGGTCCTTATGGCCAAGGCCCTTAGATTTTGCCCGCCCTTTCCCACAGTTACACATAGTACCATGGCACACTCACTGGCAATGTATCGCATATTCTTGATGCGGGGTCTGACCAAGAAGCACAATCTATGAGAGAGAAAGAAAAAAAAACAGTGAAGAAGAATTATCAAGTTGGATAGCAACTTAGAAGAAACTGAAACAATACCAACTCTTTTGCCATTTGCCCTACAGGTCTCATCCTAGCCAAAGCTATGCTATTCTCTTGGTCCACCATATACCAACCACAGAAGATACCTCTCAACACAATGGGTATAATGTGATGAGCTGGGTACATTACTGGCCCTATGGTGGACCCAAAAGTTCCTGTTCTCAAATAATTTACAATCCAGTGGGCAAAAAAAGATGCAGATATGGAGTATATTAACAATCAGTGCTGAAAAACAATATAAGAATACCCCATAAAAATATACAATTATTATCTGTCAGTTAAAAATAAAGGCTGGGCATGGTGGCTCACACCTGTAATCTTAACACTCCGGGAAGCCAAGGTGAGAAGATTGCTTGAGCTCAGGAGTTCGAAACTAGCCTCAGCAACACAGTGAGACCTCATCTCTATTAAAAATAATAATAGTGCTGTAATCCCAGCACTTTGGGAGGCAGAGGCGCGTGGATCACCTGAGGTCAGGAGTTTGAGACCAGCCCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 88857.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.240-577_290-156del		exon_loss_variant, splice_acceptor_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 4 of 23	ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.240-577_290-156del		exon_loss_variant, splice_acceptor_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 4 of 23	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.240-577_290-156del		splice_acceptor_variant, splice_donor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 4 of 35			ENSP00000494429.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Arthrogryposis, renal dysfunction, and cholestasis 1 Pathogenic:1

Dec 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555460030; hg19: chr15-91557256;