Classification rationale

BP7 VUS

BCOR c.4677C>T

The BCOR c.4677C>T (p.Asp1559=) variant has been reported in ClinVar with benign and likely benign classifications from two single submitters.¹ This variant is present in gnomAD v2.1 and v4.1 at low frequency (0.00444%-0.00448%), which is below the default BS1 threshold of 0.3% and BA1 threshold of 1.0%, so population frequency alone does not establish a stand-alone or strong benign criterion.² SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.00, supporting a benign splicing interpretation consistent with BP7.³ Cancer Hotspots did not identify a statistically significant hotspot at BCOR codon 1559, which does not support PM1.⁴

BP7 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

4 hotspots ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_017745.5 · variants mapped to exon structure

BCOR NM_017745.5

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 20 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP7 supporting Benign

This is a synonymous BCOR variant, p.(Asp1559=), and SpliceAI predicts no significant splice impact with a max delta score of 0.00. Available evidence supports BP7.

Synonymous protein consequence p.(Asp1559=).SpliceAI max delta score 0.00.

spliceai ↗

Assessed · not applied · 6 not met · 14 not assessed

Pathogenic

PVS1 BCOR loss of function is an established disease mechanism at the gene level, but this variant is a synonymous change, p.(Asp1559=), outside the default generic PVS1 null-variant categories and SpliceAI predicts no significant splice effect (max delta score 0.00).

PS2 No confirmed de novo occurrence was identified for this variant, and no parental testing data were available.

PS3 No published functional or RNA study for this exact variant was identified, so PS3 cannot be assessed.

PS4 No enrichment data or repeated observations in affected individuals were identified for this variant, so PS4 is not established.

PM1 Cancer Hotspots did not identify this residue as a statistically significant hotspot, and no evidence was identified that codon 1559 lies in a well-established critical region without benign variation.

PM2 This variant is present in gnomAD v2.1 at 0.00444% (8/180244 alleles) and in gnomAD v4.1 at 0.00448% (54/1206535 alleles).

PM3 No allelic phase data or recessive case observations were identified for this variant, so PM3 cannot be assessed.

PM6 No assumed de novo report was identified for this variant, so PM6 cannot be assessed.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed.

PP3 Available computational evidence does not support a damaging effect.

PP4 No phenotype-specific clinical data were provided to determine whether the observed features are highly specific for a BCOR-related disorder.

PP5 Although ClinVar includes submissions for this variant, PP5 was not applied because submitter assertions alone were not used as independent pathogenic evidence.

Benign

BA1 The highest observed population frequency is 0.00878% in gnomAD v4.1 Admixed American samples, which is below the 1.0% BA1 threshold.

BS1 The highest observed population frequency is 0.00878% in gnomAD v4.1, which is below the default 0.3% BS1 threshold.

BS2 Population database observations alone do not establish that this variant is seen in clearly unaffected individuals at a level sufficient for BS2, so BS2 was not applied.

BS3 No well-established functional or RNA study showing no damaging effect was identified for this variant, so BS3 cannot be assessed.

BS4 No non-segregation data were identified for this variant, so BS4 cannot be assessed.

BP2 No phase data or alternate pathogenic variant data were identified, so BP2 cannot be assessed.

BP5 No evidence was identified for an alternate molecular explanation for disease, so BP5 cannot be assessed.

BP6 ClinVar includes benign and likely benign classifications for this variant, but BP6 was not applied because submitter assertions alone were not used as independent benign evidence.

N/A · 7 PS1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP4

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 4.47563e-05; MAF= 0.00448%, 54/1206535 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.78272e-05; MAF= 0.00878%, 4/45544 alleles, homozygotes = 0); grpmax FAF= 3.948e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.43843e-05; MAF= 0.00444%, 8/180244 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.46649e-05; MAF= 0.00747%, 6/80359 alleles, homozygotes = 0); grpmax FAF= 3.178e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0045% · 54 / 1,206,535
0 hom · FAF 0.0039%

Admixed American 4 / 45,544	0.0088%
European (non-Finnish) 46 / 892,975	0.0052%
Remaining individuals 2 / 47,508	0.0042%
African/African American 2 / 56,928	0.0035%

+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0044% · 8 / 180,244
0 hom · FAF 0.0032%

European (non-Finnish) 6 / 80,359	0.0075%
Admixed American 2 / 27,190	0.0074%

+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

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 ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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