NM_017745.5:c.519C>T

BCOR · NP_060215.4:p.(Ser173=) · NM_017745.5

GRCh37: chrX:39934080 G>A · GRCh38: chrX:40074827 G>A

Gene: BCOR Transcript: NM_017745.5

Final call

Likely Benign

BP6 supporting benign BP7 supporting benign

Variant details

Gene

BCOR

Transcript

NM_017745.5

Protein

NP_060215.4:p.(Ser173=)

gnomAD AF

0.0003504468196951113 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_017745.5:c.519C>T is a synonymous variant (p.Ser173=) in exon 4 of BCOR that does not alter the protein sequence.

SpliceAI predicts no impact on splicing (max delta score 0.00), consistent with BP7 (Supporting Benign).

Three clinical laboratories in ClinVar classify this variant as Likely Benign, consistent with BP6 (Supporting Benign).

The variant is observed in gnomAD at 0.035% in v4.1 (424 alleles) with no homozygotes, which is below the PM2 threshold of 0.1% but also below the BS1 threshold of 0.3%; population frequency is uninformative for this synonymous variant.

No pathogenic or likely pathogenic ClinVar submissions, no functional evidence of damaging effect, and no segregation, de novo, or case-control data were identified to support a pathogenic classification.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	N/A	Synonymous variant (p.Ser173=) with no predicted null effect on the protein. The ClinGen SVI PVS1 decision tree does not apply to synonymous variants that do not affect splicing; variant_bucket is 'other'.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Synonymous variant; PS1 requires a different nucleotide change at the same amino acid position that is known to be pathogenic. A synonymous change with no amino acid alteration cannot meet PS1 semantics.
PS2	Not met	No de novo evidence identified in ClinVar submissions, literature review, or population data. No family studies reporting de novo occurrence of this variant were found.	clinvar
PS3	Not met	No functional studies demonstrating a damaging effect on the gene or gene product have been identified. The sole literature PMID (25741868) is the ACMG/AMP guidelines document and contains no variant-specific functional data. OncoKB lists oncogenicity as 'Unknown Oncogenic Effect' with no supporting functional publications.	PMID:25741868 oncokb
PS4	Not met	No case-control enrichment data or statistically significant excess of variant in affected individuals versus controls. The variant is observed in gnomAD at 0.017-0.035% (34-424 alleles), consistent with a population polymorphism rather than a disease-associated variant. No clinical series or cohort studies comparing affected vs. control prevalence were identified.	gnomad_v2 gnomad_v4 clinvar PMID:25741868 PMID:28492532
PS5	Not assessed	Insufficient evidence to assess PS5. No new pathogenic de novo or functional evidence has emerged that has not already been evaluated under PS2 and PS3.
PM1	Not met	This synonymous variant is located in exon 4 of BCOR (c.519). It does not lie within a recognized mutational hotspot or a critical, well-established functional domain without benign variation. The hotspots analysis confirms no statistically significant hotspot at this residue and no enrichment at this position.
PM2	Not met	The variant is present in gnomAD with 34 alleles in v2.1 (AF 0.017%) and 424 alleles in v4.1 (AF 0.035%). While below the generic 0.1% PM2 threshold, the observation of 424 alleles in a general population database for a synonymous variant on the X chromosome is not consistent with a rare pathogenic variant. PM2 is not applied.	gnomad_v2 gnomad_v4
PM5	N/A	Synonymous variant (p.Ser173=); PM5 requires a different amino acid change at the same residue that is known to be pathogenic. With no amino acid change, same-residue comparator analysis is not applicable.	pm5_candidates
PM6	Not met	No de novo occurrence (with maternity and paternity confirmed) has been reported for this variant in the reviewed literature or ClinVar submissions.	clinvar
PP1	Not met	No cosegregation data available. No family studies demonstrating segregation of this variant with a BCOR-related phenotype were identified in the literature or ClinVar submissions.	clinvar
PP2	Not met	BCOR is not established as a gene with a low rate of benign missense variation where missense changes are a common mechanism of disease. Furthermore, this is a synonymous variant; PP2 specifically addresses missense variant constraint.
PP3	Not met	No in silico evidence supports a pathogenic effect. REVEL and BayesDel scores are unavailable for this variant. SpliceAI predicts no splicing impact (max delta = 0.00). Multiple in silico tools are not available to support pathogenicity.	spliceai
PP4	Not met	No patient phenotype data specific to a BCOR-related disorder is available for review. The ClinVar submissions list 'not specified' or 'BCOR-related condition' as indications, and no detailed clinical phenotype is described that is highly specific for BCOR-related disease.	clinvar
PP5	Not met	No reputable source classifies this variant as pathogenic. In ClinVar, three clinical laboratories classify this variant as Likely Benign (Labcorp/Invitae, PreventionGenetics, CeGaT) and one classifies it as Uncertain Significance (University of Chicago). No expert panel or strong diagnostic laboratory has asserted pathogenicity.	clinvar
BA1	Not met	Maximum population allele frequency is 0.043% (NFE in gnomAD v4.1), well below the 1% BA1 threshold. This variant is not common enough to be considered a benign polymorphism by allele frequency alone.	gnomad_v2 gnomad_v4
BS1	Not met	Maximum population allele frequency is 0.043% (NFE in gnomAD v4.1), below the 0.3% BS1 threshold for non-VCEP assessment. The variant is not sufficiently common in the general population to meet BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations in gnomAD (0 homozygotes across v2.1 and v4.1). BCOR is on chromosome X, further complicating homozygosity interpretation. No evidence of this variant observed in a healthy adult in a homozygous state, or in trans with a pathogenic variant.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating no deleterious effect have been identified. The reviewed literature (PMID:25741868) is a methodological guidelines document and contains no variant-specific functional data. While SpliceAI predicts no splicing impact, a single in silico prediction tool is insufficient to meet BS3 threshold.	PMID:25741868 spliceai
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease in affected family members. No families with discordant segregation patterns have been identified.
BP1	N/A	Synonymous variant; BP1 applies specifically to missense variants where a different missense at the same position is known to be benign and the gene mechanism is truncating. Not applicable to synonymous changes.
BP2	Not met	No evidence of this variant observed in trans with a known pathogenic BCOR variant. No phase data available from ClinVar submissions or literature.	clinvar
BP4	Not met	Insufficient multiple lines of computational evidence to classify as benign. While SpliceAI predicts no splice impact (delta 0.00), REVEL and BayesDel scores are unavailable. A single neutral in silico score does not constitute multiple lines of evidence for BP4. BP7 is the more appropriate criterion for a synonymous variant with a benign splicing prediction.	spliceai
BP5	Not met	No case reports identifying this variant in an individual with an alternative molecular basis for disease have been identified. No evidence of a different pathogenic variant explaining the phenotype in a carrier of this variant.
BP6	Met	Three independent clinical laboratories classify this variant as Likely Benign in ClinVar (Labcorp/Invitae SCV002392005, PreventionGenetics SCV004781451, CeGaT SCV004164852). While these are single-submitter assertions without expert panel review, the consistent direction across multiple clinical testing laboratories provides supporting evidence for a benign assessment.	clinvar
BP7	Met	Synonymous variant (p.Ser173=) with SpliceAI delta score of 0.00 across all categories (donor gain 0.00, donor loss 0.00, acceptor gain 0.00, acceptor loss 0.00), predicting no impact on splicing. The variant does not affect the splice consensus sequence nor create a novel splice site.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.