rs201850378

chr18-21815724-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_020774.4(MIB1):c.1588C>T(p.Arg530Ter) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 1.10

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]

ACMG classification

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: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chr18-21815724-C-T is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MIB1	NM_020774.4	c.1588C>T	p.Arg530Ter	stop_gained	11/21	ENST00000261537.7
MIB1	XM_047437676.1	c.1339C>T	p.Arg447Ter	stop_gained	11/21
MIB1	XM_011526098.2	c.118C>T	p.Arg40Ter	stop_gained	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MIB1	ENST00000261537.7	c.1588C>T	p.Arg530Ter	stop_gained	11/21	1	NM_020774.4	P1
MIB1	ENST00000577749.5	n.573C>T		non_coding_transcript_exon_variant	5/6	5
MIB1	ENST00000578260.1	n.391C>T		non_coding_transcript_exon_variant	2/3	4
MIB1	ENST00000578646.5	n.1565C>T		non_coding_transcript_exon_variant	11/21	2

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152082 Hom.: 0 Cov.: 31

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: 10 AN: 251356 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135842

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: 54 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 727238

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: 10 AN: 152082 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74298

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.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Left ventricular noncompaction 7 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 17, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2023	- -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2017	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 (Luxán et al., 2013). Using blood samples from affected relatives harboring R530X, Luxán 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 (Luxán 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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.59	D
MutationTaster	Benign	1.0	A
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

Other links and lift over

dbSNP: rs201850378; hg19: chr18-19395685;