rs386834088
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_017890.5(VPS13B):c.4480_4482del(p.Leu1494del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000684 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I1492I) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
VPS13B
NM_017890.5 inframe_deletion
NM_017890.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.90
Genes affected
VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_017890.5. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.4480_4482del | p.Leu1494del | inframe_deletion | 29/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.4405_4407del | p.Leu1469del | inframe_deletion | 29/62 | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000357162.7 | c.4405_4407del | p.Leu1469del | inframe_deletion | 29/62 | 1 | NM_152564.5 | P1 | |
VPS13B | ENST00000358544.7 | c.4480_4482del | p.Leu1494del | inframe_deletion | 29/62 | 1 | NM_017890.5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461750Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 727172
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cohen syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 13, 2023 | Variant summary: VPS13B c.4480_4482delCTT (p.Leu1494del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant was absent in 251054 control chromosomes. p.Leu1494del has been reported in the literature in two related individuals affected with Cohen Syndrome who were homozygous for the variant, but carried another pathogenic upstream truncating variant on one allele, allowing evaluation of the variant in the compound heterozygous state only (Seifert_2008). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic. - |
Computational scores
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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