rs140015545
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_017890.5(VPS13B):c.3116T>C(p.Met1039Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000244 in 1,613,522 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1039V) has been classified as Uncertain significance.
Frequency
Consequence
NM_017890.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.3116T>C | p.Met1039Thr | missense_variant | 22/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.3116T>C | p.Met1039Thr | missense_variant | 22/62 | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.3116T>C | p.Met1039Thr | missense_variant | 22/62 | 1 | NM_017890.5 | ||
VPS13B | ENST00000357162.7 | c.3116T>C | p.Met1039Thr | missense_variant | 22/62 | 1 | NM_152564.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00128 AC: 195AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000271 AC: 68AN: 250890Hom.: 0 AF XY: 0.000192 AC XY: 26AN XY: 135648
GnomAD4 exome AF: 0.000136 AC: 198AN: 1461194Hom.: 3 Cov.: 31 AF XY: 0.000113 AC XY: 82AN XY: 726934
GnomAD4 genome ? AF: 0.00128 AC: 195AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.00119 AC XY: 89AN XY: 74480
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | VPS13B: BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 01, 2020 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Cohen syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | VPS13B NM_017890 exon 22 p.Met1039Thr (c.3116T>C): This variant has not been reported in the literature but is present in 0.4% (98/24028) African alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs140015545). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 27, 2021 | DNA sequence analysis of the VPS13B gene demonstrated a sequence change, c.3116T>C, in exon 22 that results in an amino acid change, p.Met1039Thr. This sequence change does not appear to have been previously described in patients with VPS13B-related disorders and has been described in the gnomAD database with a low population frequency of 0.039% (dbSNP rs140015545). The p.Met1039Thr change affects a poorly conserved amino acid residue located in a domain of the VPS13B protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met1039Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Met1039Thr change remains unknown at this time. Homozygous and compound heterozygous mutations in VPS13B have been identified in patients with Cohen syndrome [MIM#216550], characterized by ID, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia and intermittent neutropenia. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 12, 2017 | The p.M1039T variant (also known as c.3116T>C), located in coding exon 21 of the VPS13B gene, results from a T to C substitution at nucleotide position 3116. The methionine at codon 1039 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
VPS13B-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 08, 2023 | 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