X-40072392-T-A

Variant names:

• chrX-40072392-T-A
• rs587778093
• NM_001123385.2:c.2954A>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001123385.2(BCOR):​c.2954A>T​(p.Tyr985Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000108 in 1,208,648 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000073 (0 hom. 3 hem.)
• Consequence: BCOR NM_001123385.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 5.87
• Publications: 3 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25791258).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000446 (5/112163) while in subpopulation AFR AF = 0.000162 (5/30798). AF 95% confidence interval is 0.0000636. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAdExome4 at 3 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.2954A>T	p.Tyr985Phe	missense	Exon 4 of 15	NP_001116857.1	Q6W2J9-1
	BCOR	NM_001437510.1		c.2954A>T	p.Tyr985Phe	missense	Exon 4 of 15	NP_001424439.1
	BCOR	NM_001438207.1		c.2954A>T	p.Tyr985Phe	missense	Exon 4 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.2954A>T	p.Tyr985Phe	missense	Exon 4 of 15	ENSP00000367705.4	Q6W2J9-1
	BCOR	ENST00000397354.7	TSL:1	c.2954A>T	p.Tyr985Phe	missense	Exon 4 of 15	ENSP00000380512.3	Q6W2J9-2
	BCOR	ENST00000378455.8	TSL:1	c.2954A>T	p.Tyr985Phe	missense	Exon 4 of 14	ENSP00000367716.4	Q6W2J9-4

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112163 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000562 AC: 1 AN: 177824 AF XY: 0.0000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000730 AC: 8 AN: 1096485 Hom.: 0 Cov.: 30 AF XY: 0.00000829 AC XY: 3 AN XY: 361941

African (AFR) AF: 0.000190 AC: 5 AN: 26380

American (AMR) AF: 0.00 AC: 0 AN: 35107

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19349

East Asian (EAS) AF: 0.00 AC: 0 AN: 30171

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40391

Middle Eastern (MID) AF: 0.000246 AC: 1 AN: 4060

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841282

Other (OTH) AF: 0.00 AC: 0 AN: 46017

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112163 Hom.: 0 Cov.: 24 AF XY: 0.0000291 AC XY: 1 AN XY: 34311

African (AFR) AF: 0.000162 AC: 5 AN: 30798

American (AMR) AF: 0.00 AC: 0 AN: 10631

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3582

South Asian (SAS) AF: 0.00 AC: 0 AN: 2709

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6155

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53198

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.24		Loss of phosphorylation at Y985 (P = 0.026)
MVP		0.49
MPC		0.88
ClinPred		0.59	D
GERP RS		5.9
Varity_R		0.49
gMVP		0.58
Mutation Taster		=98/2	polymorphism

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: rs587778093; hg19: chrX-39931645; COSMIC: COSV99059013;