NM_021946.4:c.4464C>T

BCORL1 · NP_068765.3:p.(Asp1488=) · NM_021946.4

GRCh37: chrX:129171500 C>T · GRCh38: chrX:130037525 C>T

Gene: BCORL1 Transcript: NM_021946.4

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

BCORL1

Transcript

NM_021946.4

Protein

NP_068765.3:p.(Asp1488=)

gnomAD AF

3.9885495390316966e-05 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BCORL1 NM_021946.4:c.4464C>T (p.Asp1488=) variant has not been reported in ClinVar.

This variant is present at low frequency in gnomAD, with overall allele frequencies of 0.00396% in v2.1 and 0.00399% in v4.1; the highest observed subpopulation frequency is 0.04636% in gnomAD v4.1, which is below the 0.1% PM2 threshold and below the 0.3% BS1 threshold used here.

Computational splice prediction does not support a damaging effect, as SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the variant-level splice assessment indicates that this synonymous change is not in a canonical splice-site position.

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	Not met	BCORL1 loss of function is an established germline disease mechanism, but this variant is a synonymous change, p.(Asp1488=), and the generic PVS1 assessment found that it is not a nonsense, frameshift, or canonical +/-1,2 splice-site variant. Available evidence does not support applying PVS1.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies when a different nucleotide change produces the same pathogenic amino acid substitution. This variant is synonymous and does not alter the amino acid sequence, so PS1 is not applicable.
PS2	Not assessed	No confirmed de novo observation with established maternity and paternity was identified for this variant.	clinvar
PS3	Not assessed	No well-established functional study or RNA assay was identified for this exact variant, so PS3 cannot be assessed.	oncokb spliceai
PS4	Not assessed	No enrichment data or multiple affected germline observations were identified for this exact variant, so PS4 cannot be applied.	clinvar
PM1	Not met	This synonymous variant has not been shown to lie in a well-established mutational hotspot or critical functional region without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this site.	hotspots
PM2	Met	This variant is present at low frequency in population databases. In gnomAD v2.1 the overall AF is 0.00396% and in gnomAD v4.1 the overall AF is 0.00399%; the highest observed subpopulation frequency in gnomAD v4.1 is 0.04636%, which is below the 0.1% threshold used here for PM2.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is used for recessive disorders with pathogenic variants observed in trans. No such trans configuration evidence is relevant for this single synonymous BCORL1 variant assessment.
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 change protein length.
PM5	N/A	PM5 applies to novel missense changes at an amino acid residue where a different pathogenic missense change has been established. This variant is synonymous, and PM5 candidate review did not support classic same-residue PM5 use.	pm5_candidates
PM6	Not assessed	No assumed de novo observation was identified for this variant, so PM6 cannot be assessed.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	clinvar
PP2	N/A	PP2 is a missense criterion. This variant is synonymous, so PP2 is not applicable.
PP3	Not met	Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, and the variant is not in a canonical splice-site position. REVEL, BayesDel, and HCI prior scores were not available for this variant.	spliceai pvs1_variant_assessment
PP4	Not assessed	No phenotype information specific to the tested individual was available to determine whether the clinical presentation is highly specific for a BCORL1-related disorder.
PP5	Not assessed	No reputable source classification for this exact germline variant was identified.	clinvar
BA1	Not met	The population frequency does not meet a stand-alone benign threshold. The highest observed subpopulation frequency in gnomAD v4.1 is 0.04636%, which is below the 1% BA1 threshold used here.	gnomad_v4
BS1	Not met	The population frequency is below the benign strong threshold. The highest observed subpopulation frequency in gnomAD v4.1 is 0.04636%, which is below the 0.3% BS1 threshold used here.	gnomad_v4
BS2	Not assessed	Population data show rare alleles in gnomAD, but no evidence was identified demonstrating occurrence in definitively unaffected individuals at a level sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing no damaging effect was identified for this variant.	oncokb
BS4	Not assessed	No family data were identified showing lack of segregation with disease, so BS4 cannot be assessed.	clinvar
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is synonymous, so BP1 is not applicable.
BP2	Not assessed	No phase information or co-occurrence data were identified for this variant, 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 single-nucleotide substitution, so BP3 is not applicable.
BP4	Not assessed	Computational data do not suggest splice disruption, with SpliceAI maximum delta score 0.01, but no broader multi-predictor benign framework was available for this synonymous variant beyond splice prediction alone. BP4 was therefore not separately applied.	spliceai
BP5	Not assessed	No alternate molecular basis for the phenotype was provided, so BP5 cannot be assessed.
BP6	Not assessed	No reputable source reported this exact variant as benign or likely benign.	clinvar
BP7	Met	This is a synonymous variant, p.(Asp1488=), and available computational evidence predicts no significant effect on splicing. SpliceAI shows a maximum delta score of 0.01, and the variant-level splice assessment indicates that it is not in a canonical splice consensus position, supporting BP7.	spliceai pvs1_variant_assessment

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.