rs777945715

chrX-40074747-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001123385.2(BCOR):c.599C>T(p.Thr200Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000455 in 1,098,142 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: BCOR NM_001123385.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.64

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2734186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCOR	NM_001123385.2	c.599C>T	p.Thr200Met	missense_variant	4/15	ENST00000378444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCOR	ENST00000378444.9	c.599C>T	p.Thr200Met	missense_variant	4/15	1	NM_001123385.2	P2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000381 AC: 7 AN: 183512 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67942

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000433

Gnomad SAS 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: 0.00000455 AC: 5 AN: 1098142 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 1 AN XY: 363498

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000993

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000340

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oculofaciocardiodental syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 200 of the BCOR protein (p.Thr200Met). This variant is present in population databases (rs777945715, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with BCOR-related conditions. ClinVar contains an entry for this variant (Variation ID: 582349). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.5	L;L;L;L;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.52
MutPred		0.32		Loss of catalytic residue at T200 (P = 0.0073);Loss of catalytic residue at T200 (P = 0.0073);Loss of catalytic residue at T200 (P = 0.0073);Loss of catalytic residue at T200 (P = 0.0073);Loss of catalytic residue at T200 (P = 0.0073);
MVP		0.79
MPC		0.94
ClinPred		0.34	T
GERP RS		5.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.29
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs777945715; hg19: chrX-39934000;