18-21741303-C-T

Variant names:

• chr18-21741303-C-T
• rs556617397
• NM_020774.4:c.-281C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_020774.4(MIB1):​c.-281C>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 0.00139 in 163,912 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (0 hom.)
• Consequence: MIB1 NM_020774.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.557
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 18-21741303-C-T is Benign according to our data. Variant chr18-21741303-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1691591.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00138 (209/151788) while in subpopulation NFE AF = 0.000531 (36/67814). AF 95% confidence interval is 0.000393. There are 1 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 209 AD,Unknown gene.

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.-281C>T		5_prime_UTR	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.-281C>T		5_prime_UTR	Exon 1 of 21	ENSP00000261537.6	Q86YT6
	MIB1	ENST00000955830.1		c.-281C>T		5_prime_UTR	Exon 1 of 22	ENSP00000625889.1
	MIB1	ENST00000578646.5	TSL:2	n.168-24469C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 209 AN: 151680 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000531

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00157 AC: 19 AN: 12124 Hom.: 0 Cov.: 0 AF XY: 0.00169 AC XY: 11 AN XY: 6496

African (AFR) AF: 0.00 AC: 0 AN: 416

American (AMR) AF: 0.00 AC: 0 AN: 324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 368

East Asian (EAS) AF: 0.00 AC: 0 AN: 492

South Asian (SAS) AF: 0.00 AC: 0 AN: 120

European-Finnish (FIN) AF: 0.0164 AC: 19 AN: 1160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 64

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8392

Other (OTH) AF: 0.00 AC: 0 AN: 788

GnomAD4 genome AF: 0.00138 AC: 209 AN: 151788 Hom.: 1 Cov.: 32 AF XY: 0.00202 AC XY: 150 AN XY: 74184

African (AFR) AF: 0.0000482 AC: 2 AN: 41480

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0160 AC: 168 AN: 10522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000531 AC: 36 AN: 67814

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.000121

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	0.98
PhyloP100		0.56
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

Other links and lift over

dbSNP: rs556617397; hg19: chr18-19321264;