X-40072392-T-A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

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

Scores

3
4
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 5.87

Publications

3 publications found
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]
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BCORNM_001123385.2 linkc.2954A>T p.Tyr985Phe missense_variant Exon 4 of 15 ENST00000378444.9 NP_001116857.1 Q6W2J9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BCORENST00000378444.9 linkc.2954A>T p.Tyr985Phe missense_variant Exon 4 of 15 1 NM_001123385.2 ENSP00000367705.4 Q6W2J9-1

Frequencies

GnomAD3 genomes
AF:
0.0000446
AC:
5
AN:
112163
Hom.:
0
Cov.:
24
show subpopulations
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
show subpopulations
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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000446
AC:
5
AN:
112163
Hom.:
0
Cov.:
24
AF XY:
0.0000291
AC XY:
1
AN XY:
34311
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000453

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 13, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2954A>T (p.Y985F) alteration is located in exon 4 (coding exon 3) of the BCOR gene. This alteration results from a A to T substitution at nucleotide position 2954, causing the tyrosine (Y) at amino acid position 985 to be replaced by a phenylalanine (F). The p.Y985F alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Oculofaciocardiodental syndrome Uncertain:1
Nov 15, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 133679). This variant has not been reported in the literature in individuals affected with BCOR-related conditions. This variant is present in population databases (rs587778093, gnomAD 0.006%). This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 985 of the BCOR protein (p.Tyr985Phe). -

not specified Other:1
Sep 19, 2013
ITMI
Significance:not provided
Review Status:no classification provided
Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

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;.;T;.
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
.;D;D;D;D;D
M_CAP
Benign
0.084
D
MetaRNN
Benign
0.26
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.1
M;M;M;M;.;.
PhyloP100
5.9
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-2.1
N;N;N;N;D;.
REVEL
Benign
0.19
Sift
Pathogenic
0.0
D;D;D;D;D;.
Sift4G
Benign
0.17
T;T;T;T;.;D
Polyphen
1.0
D;D;D;D;.;.
Vest4
0.57
MutPred
0.24
Loss of phosphorylation at Y985 (P = 0.026);Loss of phosphorylation at Y985 (P = 0.026);Loss of phosphorylation at Y985 (P = 0.026);Loss of phosphorylation at Y985 (P = 0.026);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

Publications

Other links and lift over

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