rs375639152

Variant names:

Variant summary

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

The NM_001123385.2(BCOR):c.3533G>A(p.Ser1178Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000992 in 1,200,173 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., 18 hem., cov: 23)

Exomes 𝑓: 0.000040 ( 0 hom. 14 hem. )

Consequence

BCOR
NM_001123385.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0790

Publications

1 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=0.0056376457).

BP6

Variant X-40063922-C-T is Benign according to our data. Variant chrX-40063922-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 599441.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000685 (75/109492) while in subpopulation AFR AF = 0.0023 (69/30000). AF 95% confidence interval is 0.00186. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 18 XL,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCOR	NM_001123385.2 link	c.3533G>A	p.Ser1178Asn	missense_variant	Exon 8 of 15	ENST00000378444.9	NP_001116857.1	Q6W2J9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCOR	ENST00000378444.9 link	c.3533G>A	p.Ser1178Asn	missense_variant	Exon 8 of 15	1	NM_001123385.2	ENSP00000367705.4		Q6W2J9-1

Frequencies

GnomAD3 genomes

AF:

0.000676

AC:

AN:

109437

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000395

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:

0.00135

GnomAD2 exomes

AF:

0.000176

AC:

AN:

175722

AF XY:

0.0000799

show subpopulations

Gnomad AFR exome

AF:

0.00195

Gnomad AMR exome

AF:

0.000223

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:

0.000229

GnomAD4 exome

AF:

0.0000403

AC:

AN:

1090681

Hom.:

Cov.:

AF XY:

0.0000392

AC XY:

AN XY:

356821

show subpopulations

African (AFR)

AF:

0.00126

AC:

AN:

26230

American (AMR)

AF:

0.000172

AC:

AN:

34845

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19214

East Asian (EAS)

AF:

0.00

AC:

AN:

29921

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53663

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40173

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4101

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

836811

Other (OTH)

AF:

0.0000875

AC:

AN:

45723

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000685

AC:

AN:

109492

Hom.:

Cov.:

AF XY:

0.000560

AC XY:

AN XY:

32166

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

30000

American (AMR)

AF:

0.000395

AC:

AN:

10133

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3460

South Asian (SAS)

AF:

0.00

AC:

AN:

2572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5613

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52674

Other (OTH)

AF:

0.00134

AC:

AN:

1498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00109

Hom.:

Bravo

AF:

0.000650

ESP6500AA

AF:

0.00248

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3533G>A (p.S1178N) alteration is located in exon 8 (coding exon 7) of the BCOR gene. This alteration results from a G to A substitution at nucleotide position 3533, causing the serine (S) at amino acid position 1178 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Jun 21, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2, BP1, BP4, BP5; This alteration was seen in a healthy adult where full penetrance of the disorder is expected at an early age, is a missense alteration in a gene for which primarily truncating variants are known to cause disease, is predicted to be tolerated by multiple functional prediction tools, and was found in a case with an alternate molecular basis for disease. -

BCOR-related disorder

Benign:1

Jan 06, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-1.1

CADD

Benign

6.8

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.083

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.61

M_CAP

Benign

0.0081

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.37

PhyloP100

0.079

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.22

REVEL

Benign

0.063

Sift

Benign

0.85

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.15

MVP

0.29

MPC

0.25

ClinPred

0.0055

GERP RS

-1.0

Varity_R

0.13

gMVP

0.091

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over