1-1623616-A-C

Variant names:

• chr1-1623616-A-C
• rs1569737833
• NM_001170687.4:c.164A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001170687.4(MIB2):​c.164A>C​(p.Gln55Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: MIB2 NM_001170687.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIB2	NM_001170687.4	c.164A>C	p.Gln55Pro	missense_variant	Exon 3 of 20	ENST00000355826.10	NP_001164158.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIB2	ENST00000355826.10	c.164A>C	p.Gln55Pro	missense_variant	Exon 3 of 20	1	NM_001170687.4	ENSP00000348081.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.509A>C (p.Q170P) alteration is located in exon 3 (coding exon 3) of the MIB2 gene. This alteration results from a A to C substitution at nucleotide position 509, causing the glutamine (Q) at amino acid position 170 to be replaced by a proline (P). 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	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.043	D;T;D;D;D;T;T;T;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D
Vest4		0.57
MVP		0.81
MPC		0.63
ClinPred		0.99	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1569737833; hg19: chr1-1558996;