rs187172641

Variant names:

• chrX-40062945-T-C
• rs187172641
• NM_001123385.2:c.3974A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001123385.2(BCOR):​c.3974A>G​(p.Lys1325Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000293 in 1,200,919 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 99 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 6 hem., cov: 22)
  • Exomes 𝑓: 0.00030 (0 hom. 93 hem.)
• Consequence: BCOR NM_001123385.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 3.82
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae), Illumina, Orphanet, ClinGen, Ambry Genetics
• 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 (MetaRNN=0.00621143).
• BP6: Variant X-40062945-T-C is Benign according to our data. Variant chrX-40062945-T-C is described in ClinVar as Benign. ClinVar VariationId is 133695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000258 (29/112368) while in subpopulation AMR AF = 0.00224 (24/10707). AF 95% confidence interval is 0.00154. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 6 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001123385.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCOR	NM_001123385.2	MANE Select	c.3974A>G	p.Lys1325Arg	missense	Exon 9 of 15	NP_001116857.1	Q6W2J9-1
	BCOR	NM_001437510.1		c.3974A>G	p.Lys1325Arg	missense	Exon 9 of 15	NP_001424439.1
	BCOR	NM_001438207.1		c.3920A>G	p.Lys1307Arg	missense	Exon 8 of 14	NP_001425136.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCOR	ENST00000378444.9	TSL:1 MANE Select	c.3974A>G	p.Lys1325Arg	missense	Exon 9 of 15	ENSP00000367705.4	Q6W2J9-1
	BCOR	ENST00000397354.7	TSL:1	c.3872A>G	p.Lys1291Arg	missense	Exon 9 of 15	ENSP00000380512.3	Q6W2J9-2
	BCOR	ENST00000378455.8	TSL:1	c.3818A>G	p.Lys1273Arg	missense	Exon 8 of 14	ENSP00000367716.4	Q6W2J9-4

Frequencies

GnomAD3 genomes AF: 0.000267 AC: 30 AN: 112314 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00234

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: 0.00

GnomAD2 exomes AF: 0.00162 AC: 262 AN: 162094 AF XY: 0.00124

Gnomad AFR exome AF: 0.000336

Gnomad AMR exome AF: 0.00987

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000143

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.000297 AC: 323 AN: 1088551 Hom.: 0 Cov.: 32 AF XY: 0.000262 AC XY: 93 AN XY: 355521

African (AFR) AF: 0.0000762 AC: 2 AN: 26244

American (AMR) AF: 0.00898 AC: 305 AN: 33957

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19262

East Asian (EAS) AF: 0.00 AC: 0 AN: 29835

South Asian (SAS) AF: 0.00 AC: 0 AN: 52667

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39937

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.00000359 AC: 3 AN: 836772

Other (OTH) AF: 0.000284 AC: 13 AN: 45760

GnomAD4 genome AF: 0.000258 AC: 29 AN: 112368 Hom.: 0 Cov.: 22 AF XY: 0.000174 AC XY: 6 AN XY: 34558

African (AFR) AF: 0.000162 AC: 5 AN: 30865

American (AMR) AF: 0.00224 AC: 24 AN: 10707

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 2699

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6193

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53265

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.000522 Hom.: 5

Bravo AF: 0.000824

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00111 AC: 134

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (2)
-	-	1	Oculofaciocardiodental syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.8
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.073
Sift	Benign	0.15	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.29
MVP		0.85
MPC		0.27
ClinPred		0.0059	T
GERP RS		4.7
Varity_R		0.16
gMVP		0.20
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs187172641; hg19: chrX-39922198; COSMIC: COSV99059038; COSMIC: COSV99059038;