rs774040250

Variant names:

• chrX-40074472-C-A
• rs774040250
• NM_001123385.2:c.874G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_001123385.2(BCOR):​c.874G>T​(p.Gly292Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,204,010 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000012 (0 hom. 9 hem.)
• Consequence: BCOR NM_001123385.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.39
• 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: Ambry Genetics, ClinGen, Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• microphthalmia, Lenz type

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38435507).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000119 (13/1091255) while in subpopulation SAS AF = 0.000226 (12/53027). AF 95% confidence interval is 0.00013. There are 0 homozygotes in GnomAdExome4. There are 9 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAdExome4 at 9 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCOR	NM_001123385.2	MANE Select	c.874G>T	p.Gly292Cys	missense	Exon 4 of 15	NP_001116857.1
	BCOR	NM_001437510.1		c.874G>T	p.Gly292Cys	missense	Exon 4 of 15	NP_001424439.1
	BCOR	NM_001438207.1		c.874G>T	p.Gly292Cys	missense	Exon 4 of 14	NP_001425136.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCOR	ENST00000378444.9	TSL:1 MANE Select	c.874G>T	p.Gly292Cys	missense	Exon 4 of 15	ENSP00000367705.4
	BCOR	ENST00000397354.7	TSL:1	c.874G>T	p.Gly292Cys	missense	Exon 4 of 15	ENSP00000380512.3
	BCOR	ENST00000378455.8	TSL:1	c.874G>T	p.Gly292Cys	missense	Exon 4 of 14	ENSP00000367716.4

Frequencies

GnomAD3 genomes AF: 0.00000887 AC: 1 AN: 112755 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000359

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000306 AC: 5 AN: 163563 AF XY: 0.0000950

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 13 AN: 1091255 Hom.: 0 Cov.: 35 AF XY: 0.0000252 AC XY: 9 AN XY: 357735

African (AFR) AF: 0.00 AC: 0 AN: 26295

American (AMR) AF: 0.00 AC: 0 AN: 34222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19225

East Asian (EAS) AF: 0.00 AC: 0 AN: 29957

South Asian (SAS) AF: 0.000226 AC: 12 AN: 53027

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40033

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838543

Other (OTH) AF: 0.00 AC: 0 AN: 45827

GnomAD4 genome AF: 0.00000887 AC: 1 AN: 112755 Hom.: 0 Cov.: 24 AF XY: 0.0000286 AC XY: 1 AN XY: 34919

African (AFR) AF: 0.00 AC: 0 AN: 31037

American (AMR) AF: 0.00 AC: 0 AN: 10779

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.000359 AC: 1 AN: 2783

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6219

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53263

Other (OTH) AF: 0.00 AC: 0 AN: 1522

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000107 AC: 13

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	Oculofaciocardiodental syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.29		Gain of sheet (P = 0.0085)
MVP		0.82
MPC		0.95
ClinPred		0.57	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.59
gMVP		0.59
Mutation Taster		=99/1	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: rs774040250; hg19: chrX-39933725; COSMIC: COSV100652992; COSMIC: COSV100652992;