rs200035428

chr18-21858593-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• 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]

ACMG classification

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 GnomAd 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: 21 AN: 152200 Hom.: 0 Cov.: 33

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: 40 AN: 251270 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135814

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.: 1 Cov.: 26 AF XY: 0.000120 AC XY: 87 AN XY: 722882

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: 21 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74482

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.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0026	T
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.33
Sift	Benign	0.69	T
Sift4G	Benign	0.19	T
Polyphen		0.68	P
Vest4		0.76
MVP		0.32
MPC		0.92
ClinPred		0.73	D
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

Other links and lift over

dbSNP: rs200035428; hg19: chr18-19438554;