rs200035428
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2
The NM_020774.4(MIB1):c.2827G>T(p.Val943Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,603,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000096 ( 1 hom. )
Consequence
MIB1
NM_020774.4 missense
NM_020774.4 missense
Scores
2
6
11
Clinical Significance
Conservation
PhyloP100: 8.07
Genes affected
MIB1 (HGNC:21086): (MIB E3 ubiquitin protein ligase 1) This gene encodes a protein containing multiple ankyrin repeats and RING finger domains that functions as an E3 ubiquitin ligase. The encoded protein positively regulates Notch signaling by ubiquitinating the Notch receptors, thereby facilitating their endocytosis. This protein may also promote the ubiquitination and degradation of death-associated protein kinase 1 (DAPK1). [provided by RefSeq, Jun 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PP5
?
Variant 18-21858593-G-T is Pathogenic according to our data. Variant chr18-21858593-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 40091.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}. Variant chr18-21858593-G-T is described in Lovd as [Likely_pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.30444857). . Strength limited to SUPPORTING due to the PP5.
BS2
?
High AC in GnomAd4 at 21 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MIB1 | NM_020774.4 | c.2827G>T | p.Val943Phe | missense_variant | 20/21 | ENST00000261537.7 | |
MIB1 | XM_047437676.1 | c.2578G>T | p.Val860Phe | missense_variant | 20/21 | ||
MIB1 | XM_011526098.2 | c.1357G>T | p.Val453Phe | missense_variant | 11/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MIB1 | ENST00000261537.7 | c.2827G>T | p.Val943Phe | missense_variant | 20/21 | 1 | NM_020774.4 | P1 | |
MIB1 | ENST00000578646.5 | n.2804G>T | non_coding_transcript_exon_variant | 20/21 | 2 | ||||
MIB1 | ENST00000695487.1 | n.1156G>T | non_coding_transcript_exon_variant | 3/4 |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152200Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000159 AC: 40AN: 251270Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135814
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GnomAD4 exome AF: 0.0000964 AC: 140AN: 1451644Hom.: 1 Cov.: 26 AF XY: 0.000120 AC XY: 87AN XY: 722882
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GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74482
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2020 | Published functional studies suggest a damaging effect (Luxan et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 23314057, 31629663, 27260948, 27285058) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
Left ventricular noncompaction 7 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2013 | - - |
MIB1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 01, 2022 | The MIB1 c.2827G>T variant is predicted to result in the amino acid substitution p.Val943Phe. This variant has been reported to segregate in a three generation pedigree with six individuals with left ventricular noncompaction (Luxán et al. 2013. PubMed ID: 23314057). This variant was also reported in individuals with dilated cardiomyopathy (Supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666; Table S6, Alimohamed et al. 2021. PubMed ID: 33662488). However, this variant was also documented in one homozygous and eight heterozygous unrelated Turkish individuals with unknow phenotypes in a population-based study (Dataset S4, Kars et al. 2021. PubMed ID: 34426522). Functional studies indicate this variant results in a reduction of JAG1 ubiquitination when co-expressed with wild type MIB1 and injection of mRNA with this variant into zebrafish embryos may disrupt normal cardiac development (Luxán et al. 2013. PubMed ID: 23314057). This variant is reported in 0.054% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-19438554-G-T) and has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain to pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/40091). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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