rs369432845

chrX-40062275-G-AchrX-40062275-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001123385.2(BCOR):c.4292C>T(p.Ser1431Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000896 in 111,557 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1431Y) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 21)
• Consequence: BCOR NM_001123385.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-40062275-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402203.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29132286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCOR	NM_001123385.2	c.4292C>T	p.Ser1431Phe	missense_variant	10/15	ENST00000378444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCOR	ENST00000378444.9	c.4292C>T	p.Ser1431Phe	missense_variant	10/15	1	NM_001123385.2	P2

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111557 Hom.: 0 Cov.: 21 AF XY: 0.0000296 AC XY: 1 AN XY: 33727

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111557 Hom.: 0 Cov.: 21 AF XY: 0.0000296 AC XY: 1 AN XY: 33727

Gnomad4 AFR AF: 0.00

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: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	22
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;.;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D;D;D;D;D;D;D
Sift4G	Uncertain	0.030	D;D;T;D;T;T;D
Polyphen		0.65, 0.66	.;.;P;P;P;P;.
Vest4		0.38, 0.33, 0.33, 0.27, 0.29
MutPred		0.21		.;.;.;.;Loss of phosphorylation at S1431 (P = 0.0292);.;.;
MVP		0.65
MPC		0.50
ClinPred		0.65	D
GERP RS		5.7
Varity_R		0.30
gMVP		0.31

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

Other links and lift over

dbSNP: rs369432845; hg19: chrX-39921528;