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.1 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).2 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.3 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.4 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).5
BCORL1
Final classification
VUS
BCORL1 c.4642C>T · p.Arg1548Trp
BCORL1
NM_021946.4:c.4642C>T (p.Arg1548Trp) is a missense variant in BCORL1, a transcriptional corepressor located on chromosome Xq26.1.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
BCORL1 c.4642C>T
PM2 + BP4
→
VUS
Gene diagram
· NM_021946.4 · variants mapped to exon structure
BCORL1
NM_021946.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: AF=0.03072%63/205063 alleles0 homozygotes.
✓
BP4
supporting
Benign
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: 0.00572 (benign prediction).SpliceAI: max delta 0.02 (no predicted splicing impact).
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at residue 1548 resulting in an established pathogenic variant.
PS2
No de novo occurrence data available for this variant.
PS3
No variant-specific functional data available.
PS4
No case-control or statistical enrichment data available for this variant.
PM1
Residue 1548 is not in a statistically significant cancer hotspot per cancerhotspots.org.
PM5
No pathogenic missense variant identified at the same residue (Arg1548) to serve as a comparator for PM5.
PM6
No de novo occurrence data available; paternity not confirmed.
PP1
No cosegregation data available for this variant.
PP2
Missense constraint (z-score) data for BCORL1 was not available in the evidence files.
PP3
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.
PP4
No specific patient phenotype data available for comparison with BCORL1-related disorder spectrum.
PP5
ClinVar review status is 'criteria provided, single submitter' (not 3-star expert panel).
Benign
BA1
Overall allele frequency in gnomAD (v2.1: 0.03072%, v4.1: 0.03812%) is well below the 1% BA1 threshold.
BS1
Overall allele frequency in gnomAD (v2.1: 0.03072%, v4.1: 0.03812%) is well below the 0.3% BS1 threshold.
BS2
No data on observation of this variant in healthy adults beyond gnomAD population data.
BS3
No well-established functional studies demonstrating no damaging effect for this variant.
BS4
No nonsegregation data available for this variant.
BP1
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.
BP5
No alternate molecular basis for disease has been identified in a case harboring this variant.
BP6
ClinVar review status is 'criteria provided, single submitter' (not 3-star expert panel).
N/A · 6
PVS1 · PM3 · PM4 · BP2 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000381165; MAF= 0.03812%, 461/1209451 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000669038; MAF= 0.06690%, 38/56798 alleles, homozygotes = 0); grpmax FAF= 0.00050041.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000307223; MAF= 0.03072%, 63/205063 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00120659; MAF= 0.12066%, 23/19062 alleles, homozygotes = 0); grpmax FAF= 0.00082459.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.000829646017699115, 12/14464 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.038%
· 461 / 1,209,451
0 hom · FAF 0.05%
0 hom · FAF 0.05%
South Asian 38 / 56,798 |
0.067% |
European (non-Finnish) 389 / 894,834 |
0.043% |
Remaining individuals 20 / 47,597 |
0.042% |
African/African American 11 / 57,151 |
0.019% |
Admixed American 3 / 45,708 |
0.0066% |
+ 5 not observed (European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.031%
· 63 / 205,063
0 hom · FAF 0.082%
0 hom · FAF 0.082%
South Asian 23 / 19,062 |
0.12% |
Remaining individuals 5 / 5,328 |
0.094% |
European (non-Finnish) 30 / 92,512 |
0.032% |
African/African American 3 / 19,021 |
0.016% |
Admixed American 2 / 28,033 |
0.0071% |
+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
0.083%
· 12 / 14,464
0 hom · FAF 0.066%
0 hom · FAF 0.066%
European (non-Finnish) 11 / 9,395 |
0.12% |
South Asian 1 / 991 |
0.1% |
+ 7 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 3047703)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.00572034.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BCORL1, a transcriptional repressor, is recurrently mutated in hematopoietic malignancies, astrocytomas, and intracranial germ cell tumors.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV113432302, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links