NM_005180.9:c.563C>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• Publications: 0 publications found

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

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 (MetaRNN=0.23838577).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005180.9. 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
	BMI1	NM_005180.9	MANE Select	c.563C>T	p.Thr188Ile	missense	Exon 8 of 10	NP_005171.4
	COMMD3-BMI1	NM_001204062.2		c.992C>T	p.Thr331Ile	missense	Exon 12 of 14	NP_001190991.1	R4GMX3
	BMI1	NM_001428309.1		c.563C>T	p.Thr188Ile	missense	Exon 8 of 10	NP_001415238.1	P35226

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMI1	ENST00000376663.8	TSL:1 MANE Select	c.563C>T	p.Thr188Ile	missense	Exon 8 of 10	ENSP00000365851.3	P35226
	COMMD3-BMI1	ENST00000602390.5	TSL:2	c.992C>T	p.Thr331Ile	missense	Exon 12 of 14	ENSP00000473391.1	R4GMX3
	BMI1	ENST00000895844.1		c.563C>T	p.Thr188Ile	missense	Exon 9 of 11	ENSP00000565903.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L
PhyloP100		3.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.054
Sift	Benign	0.16	T
Sift4G	Benign	0.30	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
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs921071829; hg19: chr10-22617620;