NM_021946.4:c.4642C>T

BCORL1 · NP_068765.3:p.(Arg1548Trp) · NM_021946.4

GRCh37: chrX:129184715 C>T · GRCh38: chrX:130050740 C>T

Gene: BCORL1 Transcript: NM_021946.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

BCORL1

Transcript

NM_021946.4

Protein

NP_068765.3:p.(Arg1548Trp)

gnomAD AF

0.00038116467719651314 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_021946.4:c.4642C>T (p.Arg1548Trp) is a missense variant in BCORL1, a transcriptional corepressor located on chromosome Xq26.1.

This variant is present in gnomAD at very low frequency: v2.1 overall AF=0.03072% (63/205,063 alleles) and v4.1 overall AF=0.03812% (461/1,209,451 alleles), meeting PM2 at supporting level (PM2_Supporting). No homozygotes have been observed.

Multiple in silico tools predict a benign effect: BayesDel score 0.00572 is strongly benign-leaning and SpliceAI max delta 0.02 predicts no splicing impact, meeting BP4 at supporting benign level (BP4_Supporting).

The variant has been reported in ClinVar as Uncertain significance (Ambry Genetics, criteria provided, single submitter) and Likely benign (PreventionGenetics, no assertion criteria). No expert panel review is available. Neither PP5 nor BP6 criteria are met.

No variant-specific functional data, de novo reports, case-control studies, cosegregation data, or publications mentioning this exact variant were identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence.

The combined criteria yield 1 supporting pathogenic (PM2_Supporting) and 1 supporting benign (BP4_Supporting), which are balanced. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868), the final classification is Variant of Uncertain Significance (VUS).

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	N/A	Missense substitution (p.Arg1548Trp) is not a null variant; PVS1 framework (PMC6185798) does not apply to missense variants.	pvs1_generic_framework
PS1	Not met	No evidence of a different nucleotide change at residue 1548 resulting in an established pathogenic variant.
PS2	Not met	No de novo occurrence data available for this variant.
PS3	Not met	No variant-specific functional data available. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. BayesDel score (0.00572) is benign-leaning. No publications identified with functional characterization of this variant.	oncokb bayesdel
PS4	Not met	No case-control or statistical enrichment data available for this variant.
PS5	Not met	No reputable source reports this variant as pathogenic. ClinVar classifications are Uncertain significance (Ambry Genetics, criteria provided) and Likely benign (PreventionGenetics, no assertion criteria).	clinvar
PM1	Not met	Residue 1548 is not in a statistically significant cancer hotspot per cancerhotspots.org. No domain-level functional evidence specific to this residue was identified in the available data.
PM2	Met	Present in gnomAD at very low frequency: v2.1 overall AF=0.03072% (63/205,063 alleles) and v4.1 overall AF=0.03812% (461/1,209,451 alleles), both below the 0.1% PM2 threshold. No homozygotes observed. SAS subpopulation AF in v2.1 (0.12%) slightly exceeds threshold but grpmax FAF (0.082%) is below 0.1%.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic missense variant identified at the same residue (Arg1548) to serve as a comparator for PM5. Automated candidate harvesting found no same-residue pathogenic variants in ClinVar.
PM6	Not met	No de novo occurrence data available; paternity not confirmed.
PP1	Not met	No cosegregation data available for this variant.
PP2	Not assessed	Missense constraint (z-score) data for BCORL1 was not available in the evidence files. Cannot determine whether BCORL1 has a low rate of benign missense variation.
PP3	Not met	In silico tools do not support a damaging effect: BayesDel score 0.00572 is strongly benign-leaning, SpliceAI max delta 0.02 predicts no splicing impact, and REVEL is unavailable.	bayesdel spliceai
PP4	Not met	No specific patient phenotype data available for comparison with BCORL1-related disorder spectrum.
PP5	Not met	ClinVar review status is 'criteria provided, single submitter' (not 3-star expert panel). No expert panel classification as pathogenic. One submitter classified as VUS, another as Likely benign without assertion criteria.	clinvar
BA1	Not met	Overall allele frequency in gnomAD (v2.1: 0.03072%, v4.1: 0.03812%) is well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Overall allele frequency in gnomAD (v2.1: 0.03072%, v4.1: 0.03812%) is well below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No data on observation of this variant in healthy adults beyond gnomAD population data. BCORL1 is X-linked with age-related penetrance considerations; observation in healthy adults is not well characterized.
BS3	Not met	No well-established functional studies demonstrating no damaging effect for this variant. No variant-specific functional data identified.
BS4	Not met	No nonsegregation data available for this variant.
BP1	Not met	While BCORL1 loss-of-function is a supported disease mechanism, germline missense variants in BCORL1 have been reported as pathogenic (PMID:30941876, Shukla et al. 2019), demonstrating that missense is also a disease mechanism. BP1 requires that the disease mechanism is exclusively truncating.
BP2	N/A	BCORL1 is located on chromosome X; BP2 (observed in trans with a dominant pathogenic variant) does not apply to X-linked genes.
BP3	N/A	This is a missense substitution; BP3 applies to in-frame deletions/insertions in repetitive regions.
PM3	N/A	BCORL1 is X-linked; PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant.
PM4	N/A	This is a missense substitution; PM4 applies to non-repeat in-frame deletions/insertions and stop-loss variants.
BP4	Met	Multiple lines of computational evidence suggest no damaging effect: BayesDel score 0.00572 predicts a benign impact, and SpliceAI max delta 0.02 predicts no splicing alteration.	bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in a case harboring this variant.
BP6	Not met	ClinVar review status is 'criteria provided, single submitter' (not 3-star expert panel). No expert panel classification as benign or likely benign with 3-star review status.	clinvar
BP7	N/A	This is a missense variant (p.Arg1548Trp), not a synonymous variant with no predicted splicing impact. BP7 does not apply to missense substitutions.

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