X-40062969-G-A

Variant names:

• chrX-40062969-G-A
• rs780412607
• NM_001123385.2:c.3950C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001123385.2(BCOR):​c.3950C>T​(p.Pro1317Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000295 in 1,187,150 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P1317P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000030 (0 hom. 11 hem.)
• Consequence: BCOR NM_001123385.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.100
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072927177).
• BP6: Variant X-40062969-G-A is Benign according to our data. Variant chrX-40062969-G-A is described in ClinVar as Benign. ClinVar VariationId is 465160.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000268 (3/112035) while in subpopulation EAS AF = 0.000844 (3/3556). AF 95% confidence interval is 0.00023. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 11 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.3950C>T	p.Pro1317Leu	missense	Exon 9 of 15	NP_001116857.1	Q6W2J9-1
	BCOR	NM_001437510.1		c.3950C>T	p.Pro1317Leu	missense	Exon 9 of 15	NP_001424439.1
	BCOR	NM_001438207.1		c.3896C>T	p.Pro1299Leu	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.3950C>T	p.Pro1317Leu	missense	Exon 9 of 15	ENSP00000367705.4	Q6W2J9-1
	BCOR	ENST00000397354.7	TSL:1	c.3848C>T	p.Pro1283Leu	missense	Exon 9 of 15	ENSP00000380512.3	Q6W2J9-2
	BCOR	ENST00000378455.8	TSL:1	c.3794C>T	p.Pro1265Leu	missense	Exon 8 of 14	ENSP00000367716.4	Q6W2J9-4

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111984 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000841

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: 0.000128 AC: 18 AN: 140429 AF XY: 0.000139

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000298 AC: 32 AN: 1075115 Hom.: 0 Cov.: 32 AF XY: 0.0000315 AC XY: 11 AN XY: 349163

African (AFR) AF: 0.00 AC: 0 AN: 25923

American (AMR) AF: 0.0000319 AC: 1 AN: 31312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19079

East Asian (EAS) AF: 0.000926 AC: 27 AN: 29156

South Asian (SAS) AF: 0.00 AC: 0 AN: 51481

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39087

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.00000482 AC: 4 AN: 829755

Other (OTH) AF: 0.00 AC: 0 AN: 45222

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112035 Hom.: 0 Cov.: 22 AF XY: 0.0000292 AC XY: 1 AN XY: 34193

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30769

American (AMR) AF: 0.00 AC: 0 AN: 10663

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.000844 AC: 3 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53195

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000928 AC: 11

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.3
DANN	Benign	0.29
DEOGEN2	Benign	0.0063	T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.10
PrimateAI	Benign	0.29	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.086
Sift	Benign	1.0	T
Sift4G	Benign	0.32	T
Polyphen		0.0010	B
Vest4		0.11
MVP		0.39
MPC		0.27
ClinPred		0.014	T
GERP RS		-1.5
Varity_R		0.062
gMVP		0.071
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: rs780412607; hg19: chrX-39922222; COSMIC: COSV108192404; COSMIC: COSV108192404;