18-21741567-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_020774.4(MIB1):c.-17C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000783 in 1,373,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (0 hom.)
• Consequence: MIB1 NM_020774.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 3.32

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 18-21741567-C-T is Benign according to our data. Variant chr18-21741567-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1284538.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-21741567-C-T is described in Lovd as [Likely_benign]. Variant chr18-21741567-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000566 (86/151930) while in subpopulation NFE AF= 0.00105 (71/67862). AF 95% confidence interval is 0.00085. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 86 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MIB1	NM_020774.4	c.-17C>T		5_prime_UTR_variant	1/21	ENST00000261537.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MIB1	ENST00000261537.7	c.-17C>T		5_prime_UTR_variant	1/21	1	NM_020774.4	P1
MIB1	ENST00000578646.5	n.168-24205C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000566 AC: 86 AN: 151822 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00105

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000736 AC: 38 AN: 51636 Hom.: 0 AF XY: 0.000734 AC XY: 21 AN XY: 28610

Gnomad AFR exome AF: 0.000443

Gnomad AMR exome AF: 0.000689

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000864

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.00187

GnomAD4 exome AF: 0.000810 AC: 989 AN: 1221536 Hom.: 0 Cov.: 31 AF XY: 0.000758 AC XY: 451 AN XY: 595248

Gnomad4 AFR exome AF: 0.000237

Gnomad4 AMR exome AF: 0.000577

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000342

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000480

Gnomad4 NFE exome AF: 0.000948

Gnomad4 OTH exome AF: 0.000587

GnomAD4 genome AF: 0.000566 AC: 86 AN: 151930 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74264

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.00105

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs561980800; hg19: chr18-19321528;