Variant classification summary

NM_017745.5:c.4677C>T

BCOR · NP_060215.4:p.(Asp1559=) · NM_017745.5

GRCh37: chrX:39913549 G>A · GRCh38: chrX:40054296 G>A

Gene: BCOR Transcript: NM_017745.5

Final call

VUS

BP7 supporting

Variant details

Gene

BCOR

Transcript

NM_017745.5

Protein

NP_060215.4:p.(Asp1559=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BCOR c.4677C>T (p.Asp1559=) variant has been reported in ClinVar with benign and likely benign classifications from two single submitters.

2

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.

3

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.

4

Cancer Hotspots did not identify a statistically significant hotspot at BCOR codon 1559, which does not support PM1.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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). Available evidence does not support applying PVS1.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	N/A	PS1 applies to a different nucleotide change that results in the same amino acid change as an established pathogenic variant. This variant is synonymous and no such pathogenic comparison was identified.
PS2	Not assessed	No confirmed de novo occurrence was identified for this variant, and no parental testing data were available.
PS3	Not assessed	No published functional or RNA study for this exact variant was identified, so PS3 cannot be assessed.	oncokb
PS4	Not assessed	No enrichment data or repeated observations in affected individuals were identified for this variant, so PS4 is not established.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	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. PM1 is not met.	hotspots
PM2	Not met	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). Although both values are below the default 0.1% rarity threshold, the variant is not absent from population databases, so PM2 is not applied.	gnomad_v2 gnomad_v4
PM3	Not assessed	No allelic phase data or recessive case observations were identified for this variant, so PM3 cannot be assessed.
PM4	N/A	PM4 applies to protein length changes from in-frame insertions, deletions, or stop-loss variants. This variant is synonymous and does not alter protein length.
PM5	N/A	PM5 applies to a novel missense change at a residue where another pathogenic missense change has been established. This variant is not a missense change.
PM6	Not assessed	No assumed de novo report was identified for this variant, so PM6 cannot be assessed.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.
PP2	N/A	PP2 is used for missense variants in genes with a low rate of benign missense variation and a common pathogenic missense mechanism. This variant is synonymous.
PP3	Not met	Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, and no REVEL or BayesDel score was available for this synonymous variant. PP3 is not met.	spliceai
PP4	Not assessed	No phenotype-specific clinical data were provided to determine whether the observed features are highly specific for a BCOR-related disorder.
PP5	Not assessed	Although ClinVar includes submissions for this variant, PP5 was not applied because submitter assertions alone were not used as independent pathogenic evidence.	clinvar
BA1	Not met	The highest observed population frequency is 0.00878% in gnomAD v4.1 Admixed American samples, which is below the 1.0% BA1 threshold. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	The highest observed population frequency is 0.00878% in gnomAD v4.1, which is below the default 0.3% BS1 threshold. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional or RNA study showing no damaging effect was identified for this variant, so BS3 cannot be assessed.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be assessed.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are primarily pathogenic. This variant is synonymous.
BP2	Not assessed	No phase data or alternate pathogenic variant data were identified, so BP2 cannot be assessed.
BP3	N/A	BP3 applies to in-frame insertions or deletions in repetitive regions without known function. This variant is a synonymous substitution.
BP4	N/A	For this synonymous variant, the relevant benign computational assessment is captured under BP7. REVEL and BayesDel were not available, and no separate BP4 assessment was applied.	spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular explanation for disease, so BP5 cannot be assessed.
BP6	Not assessed	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.	clinvar
BP7	Met	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.	spliceai

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