Genetic Variant NM_001123385.2:c.3847+7G>A (chrX-40063601-C-T) – 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.3847+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,203,465 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.00012 ( 0 hom. 36 hem. )

Consequence

BCOR
NM_001123385.2 splice_region, intron

Scores

Splicing: ADA: 0.00002456

Clinical Significance

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

Conservation

PhyloP100: -2.99

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 (BayesDel_noAF=-0.94).

BP6

Variant X-40063601-C-T is Benign according to our data. Variant chrX-40063601-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285029.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000119 (130/1090816) while in subpopulation NFE AF = 0.000142 (119/835827). AF 95% confidence interval is 0.000121. There are 0 homozygotes in GnomAdExome4. There are 36 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 36 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	Effect	Exon Rank	Protein
BCOR	NM_001123385.2	MANE Select	c.3847+7G>A	splice_region intron	N/A	NP_001116857.1
BCOR	NM_001437510.1		c.3847+7G>A	splice_region intron	N/A	NP_001424439.1
BCOR	NM_001438207.1		c.3793+7G>A	splice_region intron	N/A	NP_001425136.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
BCOR	ENST00000378444.9	TSL:1 MANE Select	c.3847+7G>A	splice_region intron	N/A	ENSP00000367705.4
BCOR	ENST00000397354.7	TSL:1	c.3745+7G>A	splice_region intron	N/A	ENSP00000380512.3
BCOR	ENST00000378455.8	TSL:1	c.3691+7G>A	splice_region intron	N/A	ENSP00000367716.4

Frequencies

GnomAD3 genomes

AF:

0.0000266

AC:

AN:

112649

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000278

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000878

AC:

AN:

182147

AF XY:

0.0000900

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:

0.0000646

Gnomad NFE exome

AF:

0.000184

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000119

AC:

130

AN:

1090816

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

356688

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26273

American (AMR)

AF:

0.00

AC:

AN:

35172

Ashkenazi Jewish (ASJ)

AF:

0.0000518

AC:

AN:

19323

East Asian (EAS)

AF:

0.00

AC:

AN:

30184

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53870

European-Finnish (FIN)

AF:

0.000124

AC:

AN:

40174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.000142

AC:

119

AN:

835827

Other (OTH)

AF:

0.0000872

AC:

AN:

45872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.0000266

AC:

AN:

112649

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34795

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30920

American (AMR)

AF:

0.00

AC:

AN:

10762

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.000278

AC:

AN:

3594

South Asian (SAS)

AF:

0.00

AC:

AN:

2753

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

53277

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.00

Hom.:

Bravo

AF:

0.0000642

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability (1)

not provided (1)

Oculofaciocardiodental syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.010

(source)

DANN

Benign

0.47

PhyloP100

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000025

dbscSNV1_RF

Benign

0.010

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

Computational scores

Splicing

Publications

Other links and lift over