rs78992023

Variant names:

• chrX-40052404-C-A
• rs5963725
• NM_001123385.2:c.4977-4G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001123385.2(BCOR):​c.4977-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,205,271 control chromosomes in the GnomAD database, including 14,154 homozygotes. There are 70,182 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (1280 hom., 4989 hem., cov: 22)
  • Exomes 𝑓: 0.18 (12874 hom. 65193 hem.)
• Consequence: BCOR NM_001123385.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003587
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.71
• Publications: 8 publications found

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]

BCOR Gene-Disease associations (from GenCC):

• microphthalmia, syndromic 2

  Inheritance: XL, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• microphthalmia, Lenz type

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-40052404-C-A is Benign according to our data. Variant chrX-40052404-C-A is described in ClinVar as Benign. ClinVar VariationId is 95772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCOR	NM_001123385.2	c.4977-4G>T		splice_region_variant, intron_variant	Intron 14 of 14	ENST00000378444.9	NP_001116857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCOR	ENST00000378444.9	c.4977-4G>T		splice_region_variant, intron_variant	Intron 14 of 14	1	NM_001123385.2	ENSP00000367705.4

Frequencies

GnomAD3 genomes AF: 0.168 AC: 18570 AN: 110308 Hom.: 1282 Cov.: 22

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.000559

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.153

GnomAD2 exomes AF: 0.149 AC: 27117 AN: 181988 AF XY: 0.154

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.0765

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.00108

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.181 AC: 197935 AN: 1094910 Hom.: 12874 Cov.: 31 AF XY: 0.181 AC XY: 65193 AN XY: 360718

African (AFR) AF: 0.169 AC: 4463 AN: 26343

American (AMR) AF: 0.0830 AC: 2918 AN: 35157

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 3128 AN: 19367

East Asian (EAS) AF: 0.000564 AC: 17 AN: 30164

South Asian (SAS) AF: 0.192 AC: 10349 AN: 54031

European-Finnish (FIN) AF: 0.121 AC: 4918 AN: 40494

Middle Eastern (MID) AF: 0.258 AC: 1064 AN: 4128

European-Non Finnish (NFE) AF: 0.194 AC: 162800 AN: 839272

Other (OTH) AF: 0.180 AC: 8278 AN: 45954

GnomAD4 genome AF: 0.168 AC: 18561 AN: 110361 Hom.: 1280 Cov.: 22 AF XY: 0.153 AC XY: 4989 AN XY: 32647

African (AFR) AF: 0.171 AC: 5174 AN: 30345

American (AMR) AF: 0.130 AC: 1344 AN: 10333

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 410 AN: 2633

East Asian (EAS) AF: 0.000560 AC: 2 AN: 3569

South Asian (SAS) AF: 0.177 AC: 455 AN: 2575

European-Finnish (FIN) AF: 0.104 AC: 598 AN: 5743

Middle Eastern (MID) AF: 0.203 AC: 44 AN: 217

European-Non Finnish (NFE) AF: 0.192 AC: 10124 AN: 52782

Other (OTH) AF: 0.150 AC: 225 AN: 1499

Alfa AF: 0.185 Hom.: 2312

Bravo AF: 0.169

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

May 06, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oculofaciocardiodental syndrome Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Nov 24, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.27
DANN	Benign	0.67
PhyloP100		-2.7
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs5963725; hg19: chrX-39911657;