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BCOR
Final classification
Likely Pathogenic
BCOR c.3870_3871insC · p.Lys1291GlnfsTer84
BCOR ·frameshift

PVS1 (Very Strong): frameshift p.(Lys1291GlnfsTer84) is predicted to trigger nonsense-mediated decay, truncating the BCOR C-terminus.

Gene
BCOR
Transcript
NM_017745.5
HGVS · transcript:coding
NM_017745.5:c.3870_3871insC
Consequence
frameshift
exon 9
GRCh38
chrX:40062946 T>TG
GRCh37
chrX:39922199 T>TG
Basis Likely Pathogenic: 1 Very Strong (PVS1) + 1 supporting (PM2) maps to Likely Pathogenic under the ClinGen SVI 2020 PM2-downgrade rule (posterior probability 0.988). The met BP4 (splice-only, supporting) was not counted as benign evidence because it does not apply to this frameshift's loss-of-function consequence. ▾
Likely Pathogenic: 1 Very Strong (PVS1) + 1 supporting (PM2) maps to Likely Pathogenic under the ClinGen SVI 2020 PM2-downgrade rule (posterior probability 0.988). The met BP4 (splice-only, supporting) was not counted as benign evidence because it does not apply to this frameshift's loss-of-function consequence.
Classification rationale
PVS1PM2 BP4 Likely Pathogenic
BCOR c.3870_3871insC frameshift · exon 9

PVS1 (Very Strong): frameshift p.(Lys1291GlnfsTer84) is predicted to trigger nonsense-mediated decay, truncating the BCOR C-terminus. PM2 (Supporting): allele frequency 0 in gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.1% threshold. BP4 (Supporting, met but not counted): SpliceAI predicts no splice impact (max delta 0.074), but this was excluded from the combination as it does not address the frameshift consequence. Overall: Likely Pathogenic — PVS1 (Very Strong) + PM2 (Supporting) per the ClinGen SVI 2020 combination rule.

PVS1 + PM2 + BP4 → Likely Pathogenic
Gene diagram · NM_017745.5 · variants mapped to exon structure
BCOR NM_017745.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
Applied · 3
Strength Supporting Moderate Strong Very strong
✓
PVS1 very strong Pathogenic
Met (very strong): the 1-nt insertion creates frameshift p.(Lys1291GlnfsTer84) whose premature stop codon sits 753 nt upstream of the final exon-exon junction, predicted to trigger nonsense-mediated decay.
Frameshift consequence: Mutalyzer/VariantValidator normalization of NM_017745.5:c.3870_3871insC predicts NP_060215.4:p.(Lys1291GlnfsTer84) (wild-type protein 1722 aa; mutant protein 1374 aa with 84 novel out-of-frame residues), i.e., a null-variant class satisfying the first SVI PVS1 prerequisite.NMD prediction: the PTC at p.1374 (~c.4120, exon 10) is 753 nt upstream of the final exon-exon junction (exon 14/15 boundary at c.4875), far exceeding the 50-55 nt NMD threshold; the variant is in exon 9 of 15, not the last exon or the last 50 bp of the penultimate exon, so full-strength PVS1 is not excluded on NMD or location grounds.Gene-level LOF mechanism: pvs1_gene_context gate is 'eligible' (generic fallback; no BCOR CSPEC/VCEP). PMID:26847029 states 'The X-linked BCOR gene is essential for human development. Female patients harboring heterozygous mutations in BCOR develop oculofaciocardiodental (OFCD) syndrome', establishing BCOR LOF as a germline disease mechanism.
pvs1_generic_framework ↗PMID:26847029 ↗PMID:24047651 ↗
✓
PM2 supporting Pathogenic
Met (supporting): allele frequency is 0 in gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.1% threshold.
gnomAD v2.1 (exome, GRCh37): variant X-39922199-T-TG absent (search_status 'absent', AF = 0).gnomAD v4.1 (exome, GRCh38): variant X-40062946-T-TG absent (search_status 'absent', AF = 0).gnomAD-Canada v1.0 (HostSeq genomes): variant X-40062946-T-TG absent (search_status 'absent', AF = 0).
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
BP4 supporting review Benign
Met (supporting): SpliceAI max delta 0.074, below the <0.1 BP4 threshold. Flagged for human review: this reflects splice prediction only and does not contradict the frameshift's loss-of-function consequence.
SpliceAI (source key: spliceai) max delta score 0.074 is < 0.1, meeting the generic ACMG fallback BP4 threshold for non-missense variants (source key: generic_acmg_combination_rules: SpliceAI max delta < 0.1 -> BP4 supporting); the low score is consistent with the low-impact range of the SpliceAI publication (Jaganathan et al., Nat Genet 2019; PMID 30661751).BP4 here reflects only the splice-impact sub-path (no predicted splice disruption); the variant's coding consequence is a frameshift (p.Lys1291GlnfsTer84) evaluated by other groups (PVS1), so this BP4 must not be read as evidence that the gene product is unaffected.No REVEL score is available and none is used: per the generic rule, a non-missense variant has no REVEL score and there is no fallback to the missense-path predictor for the wrong variant type.
spliceai ↗
Assessed · not applied
Pathogenic
PS2 Not assessed: no proband or parental testing data were available to confirm a de novo occurrence.
PS3 Not assessed: no functional assay performed on this exact variant was available.
PS4 Not met: no case-control or cohort enrichment data exist for this exact variant.
PM3 Not assessed: no second BCOR allele or phase data were available, and BCOR germline disease is X-linked dominant, not recessive.
PM6 Not assessed: no parental testing data were available to support an unconfirmed de novo occurrence.
PP1 Not assessed: no family members were genotyped, so no segregation data were available.
PP3 Not met: SpliceAI max delta 0.074, below the >0.2 splice-altering threshold.
PP4 Not assessed: no proband phenotype or family history was available to evaluate gene-specificity.
PP5 Not met: the variant is absent from ClinVar, so no expert-panel pathogenic classification exists.
Benign
BA1 Not met: allele frequency is 0 in population databases, far below the >1% BA1 threshold.
BS1 Not met: allele frequency is 0, below the >0.3% BS1 threshold.
BS2 Not met: no healthy-adult observation exists; the variant is absent from population cohorts and ClinVar.
BS3 Not assessed: no functional study showing a benign effect of this exact variant was available.
BS4 Not assessed: no family or segregation data were available.
BP2 Not assessed: no second BCOR variant or phase information was available.
BP5 Not assessed: no proband-level workup was available to confirm or exclude an alternative molecular cause.
BP6 Not met: the variant is absent from ClinVar, so no expert-panel benign classification exists.
N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 3 further PMIDs triaged but not cited — see Sources & References.
Rule & framework references · cited for criterion definitions, not variant evidence
24047651 ↗ BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders.
26847029 ↗ BCOR regulates myeloid cell proliferation and differentiation.
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 3 PMIDs not cited in assessment
22012066 ↗ Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. ONCOKB
22237022 ↗ A novel retinoblastoma therapy from genomic and epigenetic analyses. ONCOKB
25550361 ↗ Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. ONCOKB