rs200035428

Positions:

chr18-21858593-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The ENST00000261537.7(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
ENST00000261537.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 8.07

Variant links:

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]

MIB1 links:

Genome browser will be placed here

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: {Pathogenic=1, Uncertain_significance=2}. 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	Protein
MIB1	NM_020774.4 linkuse as main transcript	c.2827G>T	p.Val943Phe	missense_variant	20/21	ENST00000261537.7	NP_065825.1
MIB1	XM_047437676.1 linkuse as main transcript	c.2578G>T	p.Val860Phe	missense_variant	20/21		XP_047293632.1
MIB1	XM_011526098.2 linkuse as main transcript	c.1357G>T	p.Val453Phe	missense_variant	11/12		XP_011524400.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MIB1	ENST00000261537.7 linkuse as main transcript	c.2827G>T	p.Val943Phe	missense_variant	20/21	1	NM_020774.4	ENSP00000261537	P1
MIB1	ENST00000578646.5 linkuse as main transcript	n.2804G>T		non_coding_transcript_exon_variant	20/21	2
MIB1	ENST00000695487.1 linkuse as main transcript	n.1156G>T		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000159

AC:

AN:

251270

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000964

AC:

140

AN:

1451644

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

722882

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000870

Gnomad4 OTH exome

AF:

0.0000833

GnomAD4 genome

AF:

0.000138

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

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

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2024	Identified in patients with LVNC or DCM in published literature ; several patients also harbored additional cardiogenetic variants (PMID: 23314057, 30847666, 33662488, 36325906); Published functional studies using a mouse model suggest that mice expressing the p.(V943F) allele develop biscupid aortic valve (BAV) in a NOTCH-sensitized genetic background and their embryonic myocardium displays LVNC features (PMID: 36325906); Published functional studies suggest reduced signaling (PMID: 23314057); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27285058, 27260948, 34426522, 33443154, 33662488, 31629663, 36325906, 23314057, 30847666) -

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.0026

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.053

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.33

Sift

Benign

0.69

Sift4G

Benign

0.19

Polyphen

0.68

Vest4

0.76

MVP

0.32

MPC

0.92

ClinPred

0.73

GERP RS

5.6

Varity_R

0.43

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over