chrX-40063653-T-C

Variant names:

• chrX-40063653-T-C
• rs140897453
• NM_001123385.2:c.3802A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001123385.2(BCOR):​c.3802A>G​(p.Arg1268Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000909 in 1,210,548 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., 18 hem., cov: 23)
  • Exomes 𝑓: 0.000046 (0 hom. 13 hem.)
• Consequence: BCOR NM_001123385.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2 O:1
• Conservation: PhyloP100: 2.69
• Publications: 3 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Illumina, Orphanet, ClinGen, Ambry Genetics
• microphthalmia, Lenz type

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.025308192).
• BP6: Variant X-40063653-T-C is Benign according to our data. Variant chrX-40063653-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133694.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000524 (59/112666) while in subpopulation AFR AF = 0.00184 (57/31005). AF 95% confidence interval is 0.00146. 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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCOR	NM_001123385.2	MANE Select	c.3802A>G	p.Arg1268Gly	missense	Exon 8 of 15	NP_001116857.1	Q6W2J9-1
	BCOR	NM_001437510.1		c.3802A>G	p.Arg1268Gly	missense	Exon 8 of 15	NP_001424439.1
	BCOR	NM_001438207.1		c.3748A>G	p.Arg1250Gly	missense	Exon 7 of 14	NP_001425136.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCOR	ENST00000378444.9	TSL:1 MANE Select	c.3802A>G	p.Arg1268Gly	missense	Exon 8 of 15	ENSP00000367705.4	Q6W2J9-1
	BCOR	ENST00000397354.7	TSL:1	c.3700A>G	p.Arg1234Gly	missense	Exon 8 of 15	ENSP00000380512.3	Q6W2J9-2
	BCOR	ENST00000378455.8	TSL:1	c.3646A>G	p.Arg1216Gly	missense	Exon 7 of 14	ENSP00000367716.4	Q6W2J9-4

Frequencies

GnomAD3 genomes AF: 0.000524 AC: 59 AN: 112611 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000186

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: 0.000120 AC: 22 AN: 182935 AF XY: 0.000104

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.000110

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: 0.0000465 AC: 51 AN: 1097882 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 13 AN XY: 363236

African (AFR) AF: 0.00140 AC: 37 AN: 26390

American (AMR) AF: 0.000199 AC: 7 AN: 35167

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4133

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841966

Other (OTH) AF: 0.0000868 AC: 4 AN: 46080

GnomAD4 genome AF: 0.000524 AC: 59 AN: 112666 Hom.: 0 Cov.: 23 AF XY: 0.000517 AC XY: 18 AN XY: 34810

African (AFR) AF: 0.00184 AC: 57 AN: 31005

American (AMR) AF: 0.000186 AC: 2 AN: 10764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3570

South Asian (SAS) AF: 0.00 AC: 0 AN: 2721

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6253

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53252

Other (OTH) AF: 0.00 AC: 0 AN: 1550

Alfa AF: 0.000164 Hom.: 8

Bravo AF: 0.000616

ESP6500AA AF: 0.00183 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	BCOR-related disorder (1)
-	1	-	not provided (1)
-	-	1	Oculofaciocardiodental syndrome (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.025	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.7
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.36
MVP		0.91
MPC		1.1
ClinPred		0.082	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.36
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs140897453; hg19: chrX-39922906; COSMIC: COSV60713620;