18-21741286-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_020774.4(MIB1):c.-298G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 158,852 control chromosomes in the GnomAD database, including 3,366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3218 hom., cov: 33)
  • Exomes 𝑓: 0.19 (148 hom.)
• Consequence: MIB1 NM_020774.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.46

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 18-21741286-G-A is Benign according to our data. Variant chr18-21741286-G-A is described in ClinVar as [Benign]. Clinvar id is 668990.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MIB1	NM_020774.4	c.-298G>A		5_prime_UTR_variant	1/21	ENST00000261537.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MIB1	ENST00000261537.7	c.-298G>A		5_prime_UTR_variant	1/21	1	NM_020774.4	P1
MIB1	ENST00000578646.5	n.168-24486G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28205 AN: 151558 Hom.: 3219 Cov.: 33

Gnomad AFR AF: 0.0925

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.192 AC: 1381 AN: 7186 Hom.: 148 Cov.: 0 AF XY: 0.191 AC XY: 735 AN XY: 3844

Gnomad4 AFR exome AF: 0.0662

Gnomad4 AMR exome AF: 0.222

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.356

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.205

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.186 AC: 28208 AN: 151666 Hom.: 3218 Cov.: 33 AF XY: 0.194 AC XY: 14399 AN XY: 74132

Gnomad4 AFR AF: 0.0924

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.399

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.194

Gnomad4 OTH AF: 0.187

Alfa AF: 0.183 Hom.: 454

Bravo AF: 0.177

Asia WGS AF: 0.392 AC: 1340 AN: 3426

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	18
Dann	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7243281; hg19: chr18-19321247; COSMIC: COSV55095387;