10-22326561-T-G

Variant names:

• chr10-22326561-T-G
• rs1836156437
• NM_005180.9:c.112T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005180.9(BMI1):​c.112T>G​(p.Phe38Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMI1 NM_005180.9 missense, splice_region
• Scores: Splicing: ADA: 0.3313
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMI1	NM_005180.9	c.112T>G	p.Phe38Val	missense_variant, splice_region_variant	Exon 2 of 10	ENST00000376663.8	NP_005171.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMI1	ENST00000376663.8	c.112T>G	p.Phe38Val	missense_variant, splice_region_variant	Exon 2 of 10	1	NM_005180.9	ENSP00000365851.3
COMMD3-BMI1	ENST00000602390.5	c.541T>G	p.Phe181Val	missense_variant, splice_region_variant	Exon 6 of 14	2		ENSP00000473391.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

See cases Uncertain:1

Nov 26, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	.;D;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T;T;T;T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.6	.;H;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.1	.;D;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Uncertain	0.038	D;D;D;D;D
Polyphen		0.98	.;D;.;.;.
Vest4		0.96
MutPred		0.85		.;Loss of stability (P = 0.0732);Loss of stability (P = 0.0732);Loss of stability (P = 0.0732);.;
MVP		0.98
MPC		1.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.95
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.33
dbscSNV1_RF	Benign	0.36
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: rs1836156437; hg19: chr10-22615490;