rs144722432

Positions:

• chrX-40073311-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001123385.2(BCOR):​c.2035G>A​(p.Val679Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000829 in 1,208,652 control chromosomes in the GnomAD database, including 1 homozygotes. There are 312 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 0.00054 (0 hom., 20 hem., cov: 24)
  • Exomes 𝑓: 0.00086 (1 hom. 292 hem.)
• Consequence: BCOR NM_001123385.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:5
• Conservation: PhyloP100: 7.57

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049465537).
• BS2: High Hemizygotes in GnomAd4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCOR	NM_001123385.2	c.2035G>A	p.Val679Ile	missense_variant	4/15	ENST00000378444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCOR	ENST00000378444.9	c.2035G>A	p.Val679Ile	missense_variant	4/15	1	NM_001123385.2	P2

Frequencies

GnomAD3 genomes AF: 0.000540 AC: 61 AN: 113058 Hom.: 0 Cov.: 24 AF XY: 0.000568 AC XY: 20 AN XY: 35196

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000463

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000479

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000918

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000668 AC: 116 AN: 173667 Hom.: 0 AF XY: 0.000550 AC XY: 33 AN XY: 59961

Gnomad AFR exome AF: 0.000240

Gnomad AMR exome AF: 0.000792

Gnomad ASJ exome AF: 0.000137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00138

GnomAD4 exome AF: 0.000859 AC: 941 AN: 1095541 Hom.: 1 Cov.: 30 AF XY: 0.000809 AC XY: 292 AN XY: 361159

Gnomad4 AFR exome AF: 0.0000759

Gnomad4 AMR exome AF: 0.00109

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000272

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.000565

GnomAD4 genome AF: 0.000539 AC: 61 AN: 113111 Hom.: 0 Cov.: 24 AF XY: 0.000567 AC XY: 20 AN XY: 35259

Gnomad4 AFR AF: 0.000128

Gnomad4 AMR AF: 0.000462

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000479

Gnomad4 NFE AF: 0.000918

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000732 Hom.: 25

Bravo AF: 0.000555

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.000586 AC: 71

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 08, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2015	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Microphthalmia, syndromic 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

- -

BCOR-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Oculofaciocardiodental syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.049	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.60	N;N;N;N;N;.
REVEL	Benign	0.097
Sift	Pathogenic	0.0	D;D;D;D;D;.
Sift4G	Benign	0.39	T;T;T;T;.;D
Polyphen		0.89	P;P;D;P;.;.
Vest4		0.48
MVP		0.52
MPC		0.83
ClinPred		0.060	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.33

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: rs144722432; hg19: chrX-39932564;