rs1555915763

Variant names:

• chrX-40064426-CTT-C
• rs1555915763
• NM_001123385.2:c.3410_3411delAA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001123385.2(BCOR):​c.3410_3411delAA​(p.Lys1137SerfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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:2
• Conservation: PhyloP100: 1.66

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]

ACMG classification

Verdict is Pathogenic. Variant got 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-40064426-CTT-C is Pathogenic according to our data. Variant chrX-40064426-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 465159.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCOR	NM_001123385.2	c.3410_3411delAA	p.Lys1137SerfsTer4	frameshift_variant	Exon 7 of 15	ENST00000378444.9	NP_001116857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCOR	ENST00000378444.9	c.3410_3411delAA	p.Lys1137SerfsTer4	frameshift_variant	Exon 7 of 15	1	NM_001123385.2	ENSP00000367705.4

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

BCOR-related disorder Pathogenic:1

Feb 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BCOR c.3410_3411delAA variant is predicted to result in a frameshift and premature protein termination (p.Lys1137Serfs*4). To our knowledge, this variant has not been reported in the literature. Loss of function variants in BCOR are known to cause oculofaciocardiodental (OFCD) syndrome in females (Hilton et al. 2009. PubMed ID: 19367324). This variant has not been reported in a large population database, indicating this variant is rare. In summary, we interpret this variant as likely pathogenic. -

Oculofaciocardiodental syndrome Pathogenic:1

Jan 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in BCOR are known to be pathogenic (PMID: 15004558, 19367324). This sequence change deletes 2 nucleotides from exon 7 of the BCOR mRNA (c.3410_3411delAA), causing a frameshift at codon 1137. This creates a premature translational stop signal (p.Lys1137Serfs*4) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555915763; hg19: chrX-39923679;