dbSNP rs111622737: BCOR:p.Val1102Gly (chrX-40064533-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001123385.2(BCOR):c.3305T>G(p.Val1102Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,210,386 control chromosomes in the GnomAD database, including 3 homozygotes. There are 52 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1102A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., 13 hem., cov: 24)

Exomes 𝑓: 0.00012 ( 3 hom. 39 hem. )

Consequence

BCOR
NM_001123385.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019565284).

BP6

Variant X-40064533-A-C is Benign according to our data. Variant chrX-40064533-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 590251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000347 (39/112363) while in subpopulation AFR AF = 0.00107 (33/30946). AF 95% confidence interval is 0.00078. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 13 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>G	p.Val1102Gly	missense	Exon 7 of 15	NP_001116857.1
BCOR	NM_001437510.1		c.3305T>G	p.Val1102Gly	missense	Exon 7 of 15	NP_001424439.1
BCOR	NM_001438207.1		c.3251T>G	p.Val1084Gly	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>G	p.Val1102Gly	missense	Exon 7 of 15	ENSP00000367705.4
BCOR	ENST00000397354.7	TSL:1	c.3305T>G	p.Val1102Gly	missense	Exon 7 of 15	ENSP00000380512.3
BCOR	ENST00000378455.8	TSL:1	c.3251T>G	p.Val1084Gly	missense	Exon 6 of 14	ENSP00000367716.4

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

112311

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000939

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000280

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:

0.00133

GnomAD2 exomes

AF:

0.000109

AC:

AN:

182652

AF XY:

0.0000445

show subpopulations

Gnomad AFR exome

AF:

0.000988

Gnomad AMR exome

AF:

0.000182

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:

0.000441

GnomAD4 exome

AF:

0.000117

AC:

129

AN:

1098023

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

363385

show subpopulations

African (AFR)

AF:

0.00227

AC:

AN:

26396

American (AMR)

AF:

0.000256

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:

841932

Other (OTH)

AF:

0.00130

AC:

AN:

46087

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000347

AC:

AN:

112363

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

34557

show subpopulations

African (AFR)

AF:

0.00107

AC:

AN:

30946

American (AMR)

AF:

0.000373

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:

0.00131

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000869

Hom.:

Bravo

AF:

0.000400

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

BCOR-related disorder

Benign:1

Jan 27, 2020

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).

History of neurodevelopmental disorder

Benign:1

Jan 15, 2013

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Oculofaciocardiodental syndrome

Benign:1

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.8

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.44

M_CAP

Benign

0.017

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.2

PhyloP100

0.34

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.070

REVEL

Benign

0.23

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.0020

Vest4

0.14

MVP

0.58

MPC

0.34

ClinPred

0.016

GERP RS

0.32

Varity_R

0.21

gMVP

0.19

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

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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