rs28989185
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_001211.6(BUB1B):āc.3035T>Cā(p.Leu1012Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000137 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1012F) has been classified as Uncertain significance.
Frequency
Consequence
NM_001211.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BUB1B | NM_001211.6 | c.3035T>C | p.Leu1012Pro | missense_variant | 23/23 | ENST00000287598.11 | |
BUB1B-PAK6 | NM_001128628.3 | c.-201+2974T>C | intron_variant | ||||
LOC107984763 | XR_001751506.2 | n.217+18844A>G | intron_variant, non_coding_transcript_variant | ||||
BUB1B-PAK6 | NM_001128629.3 | c.-118+2974T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BUB1B | ENST00000287598.11 | c.3035T>C | p.Leu1012Pro | missense_variant | 23/23 | 1 | NM_001211.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152244Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251458Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135904
GnomAD4 exome AF: 0.000150 AC: 219AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.000144 AC XY: 105AN XY: 727240
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74376
ClinVar
Submissions by phenotype
Mosaic variegated aneuploidy syndrome 1 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2004 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2023 | This missense change has been observed in individual(s) with mosaic variegated aneuploidy (PMID: 15475955, 18548531). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects BUB1B function (PMID: 20516114, 31738183). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 6765). This variant is present in population databases (rs28989185, gnomAD 0.006%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1012 of the BUB1B protein (p.Leu1012Pro). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 21, 2022 | Variant summary: BUB1B c.3035T>C (p.Leu1012Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251458 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3035T>C has been reported in the literature as a compound heterozygous genotype with another loss of function variant in at-least one individual affected with features of recessive Mosaic Variegated Aneuploidy Syndrome (Hanks_2004). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect as presented although a decrease in protein abundance was reported (Suijkerbuijk_2010). Recently, an animal mouse model of the human genotype mentioned above demonstrated that mice modeling MVA patient BUBR1X753/L1012P die during early embryogenesis (Sieben_2020). The authors conclude that a mouse model for MVA patient BUBR1X753/L1012P is unattainable, most likely due to severe mitotic defects that interfere with early embryogenesis. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Colorectal cancer;C1850343:Mosaic variegated aneuploidy syndrome 1;C1864389:Premature chromatid separation trait Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 21, 2022 | - - |
Premature chromatid separation trait Other:1
Affects, no assertion criteria provided | literature only | OMIM | Nov 01, 2004 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at