rs386834068
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM2PM4_SupportingPP3BP6BS1
The NM_152564.5(VPS13B):c.11750_11752dupATG(p.Asp3917dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,614,196 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_152564.5 disruptive_inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.11825_11827dupATG | p.Asp3942dup | disruptive_inframe_insertion | Exon 62 of 62 | ENST00000358544.7 | NP_060360.3 | |
VPS13B | NM_152564.5 | c.11750_11752dupATG | p.Asp3917dup | disruptive_inframe_insertion | Exon 62 of 62 | ENST00000357162.7 | NP_689777.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.11825_11827dupATG | p.Asp3942dup | disruptive_inframe_insertion | Exon 62 of 62 | 1 | NM_017890.5 | ENSP00000351346.2 | ||
VPS13B | ENST00000357162.7 | c.11750_11752dupATG | p.Asp3917dup | disruptive_inframe_insertion | Exon 62 of 62 | 1 | NM_152564.5 | ENSP00000349685.2 |
Frequencies
GnomAD3 genomes AF: 0.00142 AC: 216AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000387 AC: 97AN: 250636Hom.: 1 AF XY: 0.000339 AC XY: 46AN XY: 135560
GnomAD4 exome AF: 0.000230 AC: 336AN: 1461876Hom.: 1 Cov.: 31 AF XY: 0.000228 AC XY: 166AN XY: 727242
GnomAD4 genome AF: 0.00142 AC: 216AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 96AN XY: 74502
ClinVar
Submissions by phenotype
Cohen syndrome Pathogenic:1Uncertain:3Benign:1
VPS13B NM_017890.4 exon 62 p.Asp3942_dup (c.11825_11827dupATG): This variant has been reported in the literature as a compound heterozygote (in trans with a multi-exon deletion of this gene) in 1 individual with a diagnosis of Cohen syndrome (Rivera-Brugues 2011 PMID:20921020, gene identified as alternate name COH1). However, this variant is present in 0.4% (100/24024) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs558633643). This variant is present in ClinVar (Variation ID:56642). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents a duplication of 1 amino acid at position 3942 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
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not provided Uncertain:1Benign:1
In-frame insertion of one amino acid in a non-repeat region; Reported previously using alternate nomenclature (c.1827_11828insATG) in an individual with developmental delay, cardiac defects, and dysmorphic features who harbored a partial gene deletion on the opposite allele (in trans) (Rivera-Brugues et al., 2011); This variant is associated with the following publications: (PMID: 20921020) -
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Inborn genetic diseases Uncertain:1
The c.11825_11827dupATG variant (also known as p.D3942dup), located in coding exon 61 of the VPS13B gene, results from an in-frame duplication of ATG at nucleotide positions 11825 to 11827. This results in the duplication of an aspartate residue between codons 3942 and 3943. This duplication (reported as p.D3942_G3943insD) was detected in compound heterozygous state with a gross deletion encompassing exons 1 to 17 of VPS13B and exon 4 of ORS2 in a patient with developmental delay and cardiac defect (Rivera-Brugués N et al. J. Med. Genet., 2011 Feb;48:136-40). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by PROVEAN in silico analysis (Choi Y et al., PLoS ONE 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
VPS13B-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at