18-21741595-C-A

Variant names:

• chr18-21741595-C-A
• NM_020774.4:c.12C>A
• MIB1 p.Ser4Ser

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020774.4(MIB1):​c.12C>A​(p.Ser4Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S4S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MIB1 NM_020774.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• left ventricular noncompaction 7

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• isolated cleft palate

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020774.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIB1	NM_020774.4	MANE Select	c.12C>A	p.Ser4Ser	synonymous	Exon 1 of 21	NP_065825.1	Q86YT6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIB1	ENST00000261537.7	TSL:1 MANE Select	c.12C>A	p.Ser4Ser	synonymous	Exon 1 of 21	ENSP00000261537.6	Q86YT6
	MIB1	ENST00000955830.1		c.12C>A	p.Ser4Ser	synonymous	Exon 1 of 22	ENSP00000625889.1
	MIB1	ENST00000864012.1		c.12C>A	p.Ser4Ser	synonymous	Exon 1 of 20	ENSP00000534071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1407374 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 698240

African (AFR) AF: 0.00 AC: 0 AN: 30164

American (AMR) AF: 0.00 AC: 0 AN: 36000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24178

East Asian (EAS) AF: 0.00 AC: 0 AN: 34676

South Asian (SAS) AF: 0.00 AC: 0 AN: 79542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089332

Other (OTH) AF: 0.00 AC: 0 AN: 57770

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr18-19321556;