NM_021946.4:c.2361A>T

BCORL1 · NP_068765.3:p.(Pro787=) · NM_021946.4

GRCh37: chrX:129149109 A>T · GRCh38: chrX:130015133 A>T

Gene: BCORL1 Transcript: NM_021946.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

BCORL1

Transcript

NM_021946.4

Protein

NP_068765.3:p.(Pro787=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BCORL1 c.2361A>T (p.Pro787=) variant has not been reported in ClinVar.

This variant is present in gnomAD at 0.00164% in v2.1 (3/183251 alleles; grpmax FAF 9.75e-06) and 0.00107% in v4.1 (13/1212241 alleles; grpmax FAF 8.1e-06), which is below the default non-VCEP PM2 threshold of 0.1%.

SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.00, arguing against a computationally predicted splice-disrupting effect.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	This variant is synonymous at p.(Pro787=) and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site variants. Although loss of function is an established disease mechanism for BCORL1, the available evidence does not support applying PVS1 to this specific change.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	This criterion is intended for variants that produce the same amino acid change as an established pathogenic variant. This variant is synonymous and no amino acid substitution is present.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.	clinvar
PS3	Not assessed	No well-established functional or RNA study demonstrating a damaging effect of this exact variant was identified.	oncokb spliceai
PS4	Not assessed	No enrichment data in affected individuals versus controls were identified for this variant. The available sources do not provide case counts sufficient to support increased prevalence in affected individuals.	clinvar
PM1	Not met	This variant does not lie in a statistically significant hotspot, and no evidence was identified that codon 787 is in a well-established critical functional region without benign variation.	hotspots oncokb
PM2	Met	This variant is present at very low frequency in population databases and remains below the default non-VCEP PM2 threshold of 0.1%. In gnomAD v2.1 the allele frequency is 0.00164% (3/183251; grpmax FAF 9.75e-06), and in gnomAD v4.1 the allele frequency is 0.00107% (13/1212241; grpmax FAF 8.1e-06).	gnomad_v2 gnomad_v4
PM3	N/A	This criterion is used for recessive disorders with pathogenic variants observed in trans. The reviewed evidence does not support applying PM3 to this BCORL1 variant.
PM4	N/A	This variant does not change protein length and is not an in-frame insertion or deletion.
PM5	N/A	PM5 applies to novel missense changes at a residue where another pathogenic missense change is established. This variant is synonymous, and the reviewed PM5 candidate collection did not support classic same-residue PM5 use.	pm5_candidates
PM6	Not assessed	No presumed de novo report was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	N/A	PP2 is a missense-based criterion and is not applicable to this synonymous variant.
PP3	Not met	Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.	spliceai
PP4	Not assessed	No phenotype-specific clinical evidence was provided to show that the observed presentation is highly specific for BCORL1-related disease.
PP5	Not assessed	No reputable external source classification for this exact variant was identified that could support PP5.	clinvar
BA1	Not met	Population frequency does not reach the BA1 threshold of 1%. The highest reviewed population frequency is 0.00164% in gnomAD v2.1 and 0.00107% in gnomAD v4.1, both well below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not exceed the default non-VCEP BS1 threshold of 0.3%. The highest reviewed population frequency is 0.00164% in gnomAD v2.1 and 0.00107% in gnomAD v4.1, both below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	The reviewed data do not establish observation of this variant in a number of healthy individuals sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional or RNA study showing a normal effect for this exact variant was identified.	spliceai oncokb
BS4	Not assessed	No family study showing lack of segregation with disease was identified for this variant.	clinvar
BP1	N/A	BP1 is a missense-based criterion and is not applicable to this synonymous variant.
BP2	Not assessed	No phase data were identified to determine whether this variant occurs in trans with a pathogenic variant or in cis with another variant.
BP3	N/A	This criterion applies to in-frame insertions or deletions in repetitive regions and is not applicable to this synonymous single-nucleotide variant.
BP4	Met	Available computational evidence supports no predicted molecular impact. This variant is synonymous at p.(Pro787=), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00.	spliceai
BP5	Not assessed	No alternate molecular explanation for disease was identified in the reviewed materials, so BP5 was not assessed.
BP6	Not assessed	No reputable benign external classification was identified for this exact variant.	clinvar
BP7	Not assessed	This is a synonymous variant and SpliceAI predicts no significant splice impact, but the reviewed sources did not provide nucleotide conservation evidence needed for a complete BP7 assessment.	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.