Genetic Variant BCOR:p.Val1102Ala (chrX-40064533-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001123385.2(BCOR):c.3305T>C(p.Val1102Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,210,388 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1102G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., 6 hem., cov: 24)

Exomes 𝑓: 0.000015 ( 0 hom. 7 hem. )

Consequence

BCOR
NM_001123385.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.339

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021849632).

BP6

Variant X-40064533-A-G is Benign according to our data. Variant chrX-40064533-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210520.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000258 (29/112362) while in subpopulation AFR AF = 0.000905 (28/30945). AF 95% confidence interval is 0.000643. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 6 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001123385.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BCOR	NM_001123385.2	MANE Select	c.3305T>C	p.Val1102Ala	missense	Exon 7 of 15	NP_001116857.1
BCOR	NM_001437510.1		c.3305T>C	p.Val1102Ala	missense	Exon 7 of 15	NP_001424439.1
BCOR	NM_001438207.1		c.3251T>C	p.Val1084Ala	missense	Exon 6 of 14	NP_001425136.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BCOR	ENST00000378444.9	TSL:1 MANE Select	c.3305T>C	p.Val1102Ala	missense	Exon 7 of 15	ENSP00000367705.4
BCOR	ENST00000397354.7	TSL:1	c.3305T>C	p.Val1102Ala	missense	Exon 7 of 15	ENSP00000380512.3
BCOR	ENST00000378455.8	TSL:1	c.3251T>C	p.Val1084Ala	missense	Exon 6 of 14	ENSP00000367716.4

Frequencies

GnomAD3 genomes

AF:

0.000249

AC:

AN:

112310

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000874

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000933

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000274

AC:

AN:

182652

AF XY:

0.0000297

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1098026

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

363386

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40529

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841935

Other (OTH)

AF:

0.0000217

AC:

AN:

46087

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000258

AC:

AN:

112362

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

34556

show subpopulations

African (AFR)

AF:

0.000905

AC:

AN:

30945

American (AMR)

AF:

0.0000931

AC:

AN:

10736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3537

South Asian (SAS)

AF:

0.00

AC:

AN:

2717

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6189

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53157

Other (OTH)

AF:

0.00

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 12, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BCOR-related disorder

Benign:1

Feb 15, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Oculofaciocardiodental syndrome

Benign:1

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.85

CADD

Benign

4.5

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.10

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.48

M_CAP

Benign

0.011

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.55

PhyloP100

0.34

PrimateAI

Benign

0.28

PROVEAN

Benign

0.18

REVEL

Benign

0.086

Sift

Benign

0.14

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.080

MutPred

0.045

Gain of loop (P = 0.024)

MVP

0.32

MPC

0.32

ClinPred

0.018

GERP RS

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.039

gMVP

0.087

Mutation Taster

=298/2

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over