rs201850378

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2

The NM_020774.4(MIB1):c.1588C>T(p.Arg530*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,948 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

MIB1
NM_020774.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 1.10

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 Uncertain_significance. Variant got 5 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 18-21815724-C-T is Pathogenic according to our data. Variant chr18-21815724-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 40092.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}. Variant chr18-21815724-C-T is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MIB1	NM_020774.4 link	c.1588C>T	p.Arg530*	stop_gained	Exon 11 of 21	ENST00000261537.7	NP_065825.1
MIB1	XM_047437676.1 link	c.1339C>T	p.Arg447*	stop_gained	Exon 11 of 21		XP_047293632.1
MIB1	XM_011526098.2 link	c.118C>T	p.Arg40*	stop_gained	Exon 2 of 12		XP_011524400.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MIB1	ENST00000261537.7 link	c.1588C>T	p.Arg530*	stop_gained	Exon 11 of 21	1	NM_020774.4	ENSP00000261537.6	Q86YT6
MIB1	ENST00000577749.5 link	n.573C>T		non_coding_transcript_exon_variant	Exon 5 of 6	5
MIB1	ENST00000578260.1 link	n.391C>T		non_coding_transcript_exon_variant	Exon 2 of 3	4
MIB1	ENST00000578646.5 link	n.1565C>T		non_coding_transcript_exon_variant	Exon 11 of 21	2

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251356

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000369

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000567

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Left ventricular noncompaction 7

Pathogenic:4

Feb 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 17, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2024

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We observed a heterozygous NM_020774.4:c.1588C>T (p.Arg530*) genetic variant in the MIB1 gene on WES data in a sporadic case of Sudden Unexplained Nocturnal Death Syndrome (SUNDS) in 15 y.o. male adolescent. The c.1588C>T (p.Arg530*) genetic variant is in The Genome Aggregation Database (gnomAD) v2.1.1 and v4.1.0 with total MAF 0.00004598 and 0.00003965 respectively (Date of access 18-06-2023). ClinVar contains an entry for this variant (Variation ID: 40092). This variant leads to NMD of the mutant transcript according to in silico predictors and Luxán et al. (2013) experimental data (PMID: 23314057). Based on these evidences, we consider it to classify this variant as Likely Pathogenic. -

not provided

Pathogenic:2Uncertain:1

Dec 06, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R530X variant of uncertain significance in the MIB1 gene has been previously reported in one Southern European individual diagnosed with LVNC and was shown to segregate with disease in five additional affected relatives (LuxÃ¡n et al., 2013). Using blood samples from affected relatives harboring R530X, LuxÃ¡n et al. (2013) demonstrated that mutant mRNA expression is almost completely abolished and truncated MIB1 protein is not detectable, suggesting that R530X causes loss of protein expression through nonsense-mediated mRNA decay. Blood samples from these affected carriers also showed reduced NOTCH1 activity and target-gene expression (LuxÃ¡n et al., 2013). In addition, the R530X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Nevertheless, only four other variants in the MIB1 gene have been reported in HGMD in association with MIB1-related disorders, and no other truncating variants in the MIB1 gene have been reported in association with cardiomyopathy (Stenson et al., 2014). Thus, the mechanism of disease for variants in the MIB1 gene remains to be definitely established. Identification of the R530X variant in additional affected individuals, larger segregation studies, and further functional evidence are necessary to further clarify the role of this variant in disease.Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.39

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.59

Vest4

0.92

GERP RS

0.26

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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