rs375639152

chrX-40063922-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001123385.2(BCOR):c.3533G>A(p.Ser1178Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000992 in 1,200,173 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., 18 hem., cov: 23)
  • Exomes 𝑓: 0.000040 (0 hom. 14 hem.)
• Consequence: BCOR NM_001123385.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0790

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056376457).
• BP6: Variant X-40063922-C-T is Benign according to our data. Variant chrX-40063922-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 599441.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000685 (75/109492) while in subpopulation AFR AF= 0.0023 (69/30000). AF 95% confidence interval is 0.00186. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCOR	NM_001123385.2	c.3533G>A	p.Ser1178Asn	missense_variant	8/15	ENST00000378444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCOR	ENST00000378444.9	c.3533G>A	p.Ser1178Asn	missense_variant	8/15	1	NM_001123385.2	P2

Frequencies

GnomAD3 genomes AF: 0.000676 AC: 74 AN: 109437 Hom.: 0 Cov.: 23 AF XY: 0.000530 AC XY: 17 AN XY: 32105

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00135

GnomAD3 exomes AF: 0.000176 AC: 31 AN: 175722 Hom.: 0 AF XY: 0.0000799 AC XY: 5 AN XY: 62552

Gnomad AFR exome AF: 0.00195

Gnomad AMR exome AF: 0.000223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.0000403 AC: 44 AN: 1090681 Hom.: 0 Cov.: 31 AF XY: 0.0000392 AC XY: 14 AN XY: 356821

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.000172

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000875

GnomAD4 genome AF: 0.000685 AC: 75 AN: 109492 Hom.: 0 Cov.: 23 AF XY: 0.000560 AC XY: 18 AN XY: 32166

Gnomad4 AFR AF: 0.00230

Gnomad4 AMR AF: 0.000395

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00134

Alfa AF: 0.000952 Hom.: 4

Bravo AF: 0.000650

ESP6500AA AF: 0.00248 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.3533G>A (p.S1178N) alteration is located in exon 8 (coding exon 7) of the BCOR gene. This alteration results from a G to A substitution at nucleotide position 3533, causing the serine (S) at amino acid position 1178 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Jun 21, 2017

BS2, BP1, BP4, BP5; This alteration was seen in a healthy adult where full penetrance of the disorder is expected at an early age, is a missense alteration in a gene for which primarily truncating variants are known to cause disease, is predicted to be tolerated by multiple functional prediction tools, and was found in a case with an alternate molecular basis for disease. -

BCOR-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	6.8
Dann	Benign	0.37
DEOGEN2	Benign	0.083	T
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.37	N
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.063
Sift	Benign	0.85	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.29
MPC		0.25
ClinPred		0.0055	T
GERP RS		-1.0
Varity_R		0.13
gMVP		0.091

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs375639152; hg19: chrX-39923175;