chr1-1615514-A-G

Variant names:

• chr1-1615514-A-G
• rs1643515691
• NM_001170687.4:c.-249A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001170687.4(MIB2):​c.-249A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000363 in 1,377,562 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: MIB2 NM_001170687.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.783

Genes affected

MIB2 (HGNC:30577): (MIB E3 ubiquitin protein ligase 2) The protein encoded by this gene is an E3 ubiquitin protein ligase that mediates ubiquitination of proteins in the Notch signaling pathway. The encoded protein may be a suppressor of melanoma invasion. [provided by RefSeq, Mar 2017]

ENSG00000272106 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037240654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIB2	NM_001170687.4	c.-249A>G		5_prime_UTR_variant	Exon 1 of 20	ENST00000355826.10	NP_001164158.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIB2	ENST00000355826	c.-249A>G		5_prime_UTR_variant	Exon 1 of 20	1	NM_001170687.4	ENSP00000348081.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000363 AC: 5 AN: 1377562 Hom.: 0 Cov.: 32 AF XY: 0.00000735 AC XY: 5 AN XY: 679930

Gnomad4 AFR exome AF: 0.0000330

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000695

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.55A>G (p.T19A) alteration is located in exon 1 (coding exon 1) of the MIB2 gene. This alteration results from a A to G substitution at nucleotide position 55, causing the threonine (T) at amino acid position 19 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.4
DANN	Benign	0.60
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.35	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.037	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.18	N;N;N;N
REVEL	Benign	0.011
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Vest4		0.026
MutPred		0.12		Loss of phosphorylation at T19 (P = 0.0107);Loss of phosphorylation at T19 (P = 0.0107);Loss of phosphorylation at T19 (P = 0.0107);Loss of phosphorylation at T19 (P = 0.0107);
MVP		0.048
MPC		0.44
ClinPred		0.070	T
GERP RS		-0.42
gMVP		0.063

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: rs1643515691; hg19: chr1-1550894;