10-22328691-C-T

Variant names:

• chr10-22328691-C-T
• rs921071829
• NM_005180.9:c.563C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005180.9(BMI1):​c.563C>T​(p.Thr188Ile) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BMI1 NM_005180.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

Genes affected

BMI1 (HGNC:1066): (BMI1 proto-oncogene, polycomb ring finger) This gene encodes a ring finger protein that is major component of the polycomb group complex 1 (PRC1). This complex functions through chromatin remodeling as an essential epigenetic repressor of multiple regulatory genes involved in embryonic development and self-renewal in somatic stem cells. This protein also plays a central role in DNA damage repair. This gene is an oncogene and aberrant expression is associated with numerous cancers and is associated with resistance to certain chemotherapies. A pseudogene of this gene is found on chromosome X. Read-through transcription also exists between this gene and the upstream COMM domain containing 3 (COMMD3) gene. [provided by RefSeq, Sep 2015]

COMMD3-BMI1 (HGNC:48326): (COMMD3-BMI1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring COMM domain-containing protein 3 and polycomb complex protein BMI-1 genes on chromosome 10. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23838577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMI1	NM_005180.9	c.563C>T	p.Thr188Ile	missense_variant	Exon 8 of 10	ENST00000376663.8	NP_005171.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMI1	ENST00000376663.8	c.563C>T	p.Thr188Ile	missense_variant	Exon 8 of 10	1	NM_005180.9	ENSP00000365851.3
COMMD3-BMI1	ENST00000602390.5	c.992C>T	p.Thr331Ile	missense_variant	Exon 12 of 14	2		ENSP00000473391.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.992C>T (p.T331I) alteration is located in exon 12 (coding exon 12) of the COMMD3-BMI1 gene. This alteration results from a C to T substitution at nucleotide position 992, causing the threonine (T) at amino acid position 331 to be replaced by an isoleucine (I). 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
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	.;T;.
Eigen	Benign	-0.012
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	.;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.0	.;N;N
REVEL	Benign	0.054
Sift	Benign	0.16	.;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0020	.;B;.
Vest4		0.28
MutPred		0.44		.;Loss of phosphorylation at T188 (P = 0.1169);.;
MVP		0.68
MPC		0.54
ClinPred		0.79	D
GERP RS		5.6
Varity_R		0.24
gMVP		0.41

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: rs921071829; hg19: chr10-22617620;