Genetic Variant BCOR:p.Pro85Arg (chrX-40075092-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_001123385.2(BCOR):c.254C>G(p.Pro85Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000456 in 1,095,504 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P85L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

BCOR
NM_001123385.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.13

Publications

24 publications found

Variant links:

Genes affected

BCOR (HGNC:20893): (BCL6 corepressor) The protein encoded by this gene was identified as an interacting corepressor of BCL6, a POZ/zinc finger transcription repressor that is required for germinal center formation and may influence apoptosis. This protein selectively interacts with the POZ domain of BCL6, but not with eight other POZ proteins. Specific class I and II histone deacetylases (HDACs) have been shown to interact with this protein, which suggests a possible link between the two classes of HDACs. Several transcript variants encoding different isoforms have been found for this gene. A pseudogene of this gene is found on chromosome Y.[provided by RefSeq, Jun 2010]

BCOR Gene-Disease associations (from GenCC):

microphthalmia, syndromic 2
Inheritance: XL, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P
microphthalmia, Lenz type
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

BCOR links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-40075092-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10911.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCOR	NM_001123385.2 link	c.254C>G	p.Pro85Arg	missense_variant	Exon 4 of 15	ENST00000378444.9	NP_001116857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCOR	ENST00000378444.9 link	c.254C>G	p.Pro85Arg	missense_variant	Exon 4 of 15	1	NM_001123385.2	ENSP00000367705.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000559

AC:

AN:

178976

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000633

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000456

AC:

AN:

1095504

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361156

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26341

American (AMR)

AF:

0.00

AC:

AN:

35017

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19243

East Asian (EAS)

AF:

0.00

AC:

AN:

30153

South Asian (SAS)

AF:

0.00

AC:

AN:

53851

European-Finnish (FIN)

AF:

0.0000991

AC:

AN:

40371

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4119

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840451

Other (OTH)

AF:

0.0000218

AC:

AN:

45958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.;D;.;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.0

.;D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.75

D;D;D;D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.8

L;L;L;L;.

PhyloP100

7.1

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.0

D;D;D;D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Benign

0.13

T;T;T;T;.

Vest4

0.81

ClinPred

0.75

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.92

Mutation Taster

=39/61

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over