chrX-40062248-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000378444.9(BCOR):​c.4319C>T​(p.Pro1440Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000024 in 1,209,263 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P1440P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 22)
Exomes 𝑓: 0.000024 ( 0 hom. 9 hem. )

Consequence

BCOR
ENST00000378444.9 missense

Scores

1
6
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.91
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.25794947).
BS2
High Hemizygotes in GnomAdExome4 at 9 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BCORNM_001123385.2 linkuse as main transcriptc.4319C>T p.Pro1440Leu missense_variant 10/15 ENST00000378444.9 NP_001116857.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BCORENST00000378444.9 linkuse as main transcriptc.4319C>T p.Pro1440Leu missense_variant 10/151 NM_001123385.2 ENSP00000367705 P2Q6W2J9-1

Frequencies

GnomAD3 genomes
AF:
0.0000269
AC:
3
AN:
111513
Hom.:
0
Cov.:
22
AF XY:
0.0000297
AC XY:
1
AN XY:
33669
show subpopulations
Gnomad AFR
AF:
0.0000326
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:
0.0000377
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000111
AC:
2
AN:
180605
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
65547
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000366
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:
0.0000124
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000237
AC:
26
AN:
1097750
Hom.:
0
Cov.:
33
AF XY:
0.0000248
AC XY:
9
AN XY:
363136
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000569
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.0000434
GnomAD4 genome
AF:
0.0000269
AC:
3
AN:
111513
Hom.:
0
Cov.:
22
AF XY:
0.0000297
AC XY:
1
AN XY:
33669
show subpopulations
Gnomad4 AFR
AF:
0.0000326
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000377
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000831

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 16, 2024The c.4319C>T (p.P1440L) alteration is located in exon 10 (coding exon 9) of the BCOR gene. This alteration results from a C to T substitution at nucleotide position 4319, causing the proline (P) at amino acid position 1440 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Oculofaciocardiodental syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 13, 2022This missense change has been observed in individual(s) with BCOR-related conditions (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 579723). This missense change has been observed in at least one individual who was not affected with BCOR-related conditions (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1406 of the BCOR protein (p.Pro1406Leu). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.075
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.066
.;T;.;.;D;.;T
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.82
T;T;.;T;T;T;T
M_CAP
Pathogenic
0.63
D
MetaRNN
Benign
0.26
T;T;T;T;T;T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
1.7
.;.;.;.;L;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-3.1
D;D;D;D;D;D;D
REVEL
Benign
0.14
Sift
Uncertain
0.0080
D;D;T;D;D;T;D
Sift4G
Uncertain
0.023
D;D;D;D;D;D;T
Polyphen
0.040, 0.0050, 0.010
.;.;B;B;B;B;.
Vest4
0.22, 0.31, 0.33, 0.43, 0.29
MutPred
0.20
.;.;.;.;Loss of glycosylation at P1440 (P = 0.0596);.;.;
MVP
0.77
MPC
0.27
ClinPred
0.78
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.25
gMVP
0.72

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1033092772; hg19: chrX-39921501; API