rs143697110

chrX-40074720-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001123385.2(BCOR):c.626C>T(p.Ser209Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000963 in 1,209,771 control chromosomes in the GnomAD database, including 2 homozygotes. There are 382 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S209S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., 24 hem., cov: 23)
  • Exomes 𝑓: 0.00099 (2 hom. 358 hem.)
• Consequence: BCOR NM_001123385.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 9.60

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08822474).
• BP6: Variant X-40074720-G-A is Benign according to our data. Variant chrX-40074720-G-A is described in ClinVar as [Benign]. Clinvar id is 133685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-40074720-G-A is described in Lovd as [Benign]. Variant chrX-40074720-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCOR	NM_001123385.2	c.626C>T	p.Ser209Leu	missense_variant	4/15	ENST00000378444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCOR	ENST00000378444.9	c.626C>T	p.Ser209Leu	missense_variant	4/15	1	NM_001123385.2	P2

Frequencies

GnomAD3 genomes AF: 0.000744 AC: 83 AN: 111561 Hom.: 0 Cov.: 23 AF XY: 0.000711 AC XY: 24 AN XY: 33739

Gnomad AFR AF: 0.0000981

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00122

Gnomad ASJ AF: 0.00227

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000664

GnomAD3 exomes AF: 0.000583 AC: 107 AN: 183508 Hom.: 0 AF XY: 0.000662 AC XY: 45 AN XY: 67938

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000547

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000854

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000985 AC: 1082 AN: 1098160 Hom.: 2 Cov.: 35 AF XY: 0.000985 AC XY: 358 AN XY: 363514

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000653

Gnomad4 ASJ exome AF: 0.00289

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.0000493

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.000744 AC: 83 AN: 111611 Hom.: 0 Cov.: 23 AF XY: 0.000710 AC XY: 24 AN XY: 33799

Gnomad4 AFR AF: 0.0000978

Gnomad4 AMR AF: 0.00122

Gnomad4 ASJ AF: 0.00227

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.000655

Alfa AF: 0.000926 Hom.: 34

Bravo AF: 0.000763

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00208 AC: 6

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.00104

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Oculofaciocardiodental syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.088	T;T;T;T;T
MetaSVM	Uncertain	0.0073	D
MutationAssessor	Benign	1.8	L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N;N;N;N;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Benign	0.30	T;T;T;T;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.73
MVP		0.92
MPC		0.34
ClinPred		0.084	T
GERP RS		5.4
Varity_R		0.33
gMVP		0.70

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: rs143697110; hg19: chrX-39933973; COSMIC: COSV60707648; COSMIC: COSV60707648;