chrX-40064449-A-AG

Variant names:

• chrX-40064449-A-AG
• rs1555915785
• NM_001123385.2:c.3388dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001123385.2(BCOR):​c.3388dupC​(p.Leu1130ProfsTer12) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: BCOR NM_001123385.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.20
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-40064449-A-AG is Pathogenic according to our data. Variant chrX-40064449-A-AG is described in ClinVar as Pathogenic. ClinVar VariationId is 465158.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3388dupC	p.Leu1130ProfsTer12	frameshift	Exon 7 of 15	NP_001116857.1
	BCOR	NM_001437510.1		c.3388dupC	p.Leu1130ProfsTer12	frameshift	Exon 7 of 15	NP_001424439.1
	BCOR	NM_001438207.1		c.3334dupC	p.Leu1112ProfsTer12	frameshift	Exon 6 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.3388dupC	p.Leu1130ProfsTer12	frameshift	Exon 7 of 15	ENSP00000367705.4
	BCOR	ENST00000397354.7	TSL:1	c.3388dupC	p.Leu1130ProfsTer12	frameshift	Exon 7 of 15	ENSP00000380512.3
	BCOR	ENST00000378455.8	TSL:1	c.3334dupC	p.Leu1112ProfsTer12	frameshift	Exon 6 of 14	ENSP00000367716.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oculofaciocardiodental syndrome Pathogenic:1

Jul 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loss-of-function variants in BCOR are known to be pathogenic (PMID: 15004558, 19367324). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with BCOR-related disease. This sequence change creates a premature translational stop signal (p.Leu1130Profs*12) in the BCOR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555915785; hg19: chrX-39923702;