BCORL1 c.3143G>A (p.Arg1048Gln) is a missense variant in exon 3 of this X-linked transcriptional corepressor gene. This variant is present in gnomAD v4.1 at an overall allele frequency of 0.038% (464/1,210,072 alleles) and in v2.1 at 0.019% (39/205,240 alleles), with zero homozygotes observed (PM2_Supporting).1 Multiple in silico tools predict a benign effect: BayesDel score -0.289255 is in the benign range, and SpliceAI predicts no splicing alteration (max delta 0.00) (BP4_Supporting).2 No functional studies, de novo observations, case-control data, cosegregation evidence, or ClinVar classifications are available for this variant.3 With one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting), the evidence is insufficient to classify this variant as either likely pathogenic or likely benign. This variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines (PMID:25741868).4
BCORL1
Final classification
VUS
BCORL1 c.3143G>A · p.Arg1048Gln
BCORL1
BCORL1 c.3143G>A (p.Arg1048Gln) is a missense variant in exon 3 of this X-linked transcriptional corepressor gene.
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; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
BCORL1 c.3143G>A
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
This variant is present in gnomAD at extremely low frequency: v2.1 AF=0.019% (39/205,240 alleles), v4.1 AF=0.038% (464/1,210,072 alleles), grpmax FAF=0.045%. All frequencies are below the 0.1% PM2 threshold. Zero homozygotes observed in both datasets. Absent from gnomAD-Canada.
gnomAD v2.1: 39/205240 alleles (AF=0.019%). gnomAD v4.1: 464/1210072 alleles (AF=0.038%). Both below PM2 0.1% threshold. Zero homozygotes.
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on gene product or splicing. BayesDel score is -0.289255 (benign range; damaging threshold approximately >+0.07). SpliceAI max delta score is 0.00 (no predicted splicing alteration). REVEL score is unavailable but the concordance of BayesDel and SpliceAI supports a benign computational profile.
BayesDel: -0.289255 (benign). SpliceAI: max delta 0.00 (no splice impact).
Assessed · not applied
Pathogenic
PS2
No de novo observation has been reported for NM_021946.4:c.3143G>A in the available literature or databases.
PS3
No well-established in vitro or in vivo functional studies demonstrate a damaging effect for this variant.
PS4
No case-control studies or statistically significant enrichment of this variant in affected individuals versus controls has been reported.
PM1
This variant does not lie in a statistically significant somatic mutational hotspot, and there is no evidence that residue 1048 resides in a well-established critical functional domain where pathogenic missense variation clusters without benign variation.
PM5
No pathogenic or likely pathogenic missense variant at the same amino acid residue (Arg1048) with a different amino acid change was identified.
PM6
No de novo observation has been reported for this variant.
PP1
No cosegregation data are available for this variant in affected families.
PP2
Insufficient gene-level constraint data to determine whether BCORL1 has a low rate of benign missense variation.
PP3
In silico tools do not support a damaging effect.
PP4
No patient phenotype or family history information is available for the individual carrying this variant.
PP5
This variant has not been reported as pathogenic by a reputable source.
Benign
BA1
Allele frequency in gnomAD v4.1 is 0.038% (464/1,210,072 alleles), well below the 1% BA1 threshold.
BS1
Allele frequency in gnomAD v4.1 is 0.038% (464/1,210,072 alleles), below the 0.3% BS1 threshold.
BS2
Although the variant is observed in 464 alleles in gnomAD v4.1, a population database enriched for ostensibly healthy individuals, specific evidence confirming that hemizygous male carriers are unaffected is not available.
BS3
No well-established in vitro or in vivo functional studies demonstrate no damaging effect on protein function or splicing for this variant.
BS4
No non-segregation data are available for this variant in affected families.
BP1
BCORL1 missense variants have been established as a disease mechanism.
BP2
No data are available regarding observation of this variant in trans with a known pathogenic variant in BCORL1.
BP5
No case has been reported in which this variant is present alongside an alternate molecular basis for disease.
BP6
This variant has not been reported as benign by a reputable source.
N/A · 6
PVS1 · PS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000383448; MAF= 0.03834%, 464/1210072 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000483637; MAF= 0.04836%, 433/895300 alleles, homozygotes = 0); grpmax FAF= 0.0004457.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000190021; MAF= 0.01900%, 39/205240 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000750047; MAF= 0.07500%, 4/5333 alleles, homozygotes = 0); grpmax FAF= 0.00022236.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.038%
· 464 / 1,210,072
0 hom · FAF 0.045%
0 hom · FAF 0.045%
European (non-Finnish) 433 / 895,300 |
0.048% |
Remaining individuals 17 / 47,604 |
0.036% |
European (Finnish) 7 / 46,506 |
0.015% |
Admixed American 5 / 45,744 |
0.011% |
South Asian 1 / 56,867 |
0.0018% |
African/African American 1 / 57,189 |
0.0017% |
+ 4 not observed (Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.019%
· 39 / 205,240
0 hom · FAF 0.022%
0 hom · FAF 0.022%
Remaining individuals 4 / 5,333 |
0.075% |
European (non-Finnish) 27 / 92,592 |
0.029% |
European (Finnish) 3 / 18,629 |
0.016% |
Admixed American 4 / 28,054 |
0.014% |
South Asian 1 / 19,080 |
0.0052% |
+ 3 not observed (African/African American, Ashkenazi Jewish, East Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.289255.
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; COSV106354134, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links