The BCORL1 NM_021946.4:c.1111A>C (NP_068765.3:p.(Thr371Pro)) variant has not been reported in ClinVar.1 This variant is present in gnomAD v2.1 and gnomAD v4.1; in gnomAD v4.1 the highest observed population frequency is 0.21512% in African/African American samples, which is above the default 0.1% PM2 rarity threshold but below the 0.3% BS1 threshold.2 Cancer Hotspots did not identify a statistically significant hotspot at Thr371, so available evidence does not support PM1.3 Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and BayesDel is -0.610016, supporting BP4 and arguing against PP3.4 Although BCORL1 loss of function appears to be a relevant disease mechanism, this variant is a missense substitution rather than a qualifying null variant, so the generic PVS1 framework does not apply.5
Final classification
VUS
BP4
BCORL1
c.1111A>C
p.Thr371Pro
This variant
The BCORL1 NM_021946.4:c.1111A>C (NP_068765.3:p.(Thr371Pro)) variant has not been reported in ClinVar.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting; combination = 1 supporting benign, which maps to VUS.
Classification rationale
BP4
VUS
BCORL1 c.1111A>C
BP4
→
VUS
4
spliceai ↗bayesdel
5
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_021946.4 · variants mapped to exon structure
BCORL1
NM_021946.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
BP4
supporting
Benign
Available computational evidence supports no significant impact. SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, and BayesDel is -0.610016, which is not supportive of a damaging missense effect. BP4 is met.
SpliceAI max delta score 0.00BayesDel score -0.610016
Assessed · not applied
· 5 not met · 17 not assessed
Pathogenic
PS1
No pathogenic or likely pathogenic variant producing the same amino acid change was identified in the available germline database review, so PS1 cannot be established from the current evidence.
PS2
No confirmed de novo occurrence with maternity and paternity established was identified for this variant.
PS3
No well-established functional study demonstrating a damaging effect for this specific variant was identified.
PS4
No enrichment in affected individuals, case series, or multiple independent germline observations was identified for this variant.
PM1
Available hotspot review did not identify Thr371 as part of a statistically significant mutational hotspot, and no well-established critical functional domain specific to this residue was identified from the reviewed evidence.
PM2
This variant is present in gnomAD v2.1 and gnomAD v4.1.
PM5
No established same-residue pathogenic or likely pathogenic comparator was identified, and the available comparator review did not confirm a safe classic same-residue PM5 application for this gene-context review.
PM6
No presumed de novo observation without full parentage confirmation was identified for this variant.
PP1
No segregation data were identified for this variant.
PP2
The available evidence does not establish that BCORL1 is a gene in which pathogenic missense variation is a common disease mechanism with a low rate of benign missense variation, so PP2 was not assessed.
PP3
Available computational evidence does not support a damaging effect.
PP4
No individual-level phenotype information was available to determine whether the clinical presentation is highly specific for a BCORL1-related disorder.
PP5
No reputable clinical source classification for this variant was identified because the variant is absent from ClinVar.
Benign
BA1
The highest observed population frequency is 0.21512% in gnomAD v4.1, which is below the default benign stand-alone BA1 threshold of 1%, so BA1 is not met.
BS1
The highest observed population frequency is 0.21512% in gnomAD v4.1, which is below the default BS1 threshold of 0.3%, so BS1 is not met.
BS2
No evidence was identified showing this variant in unaffected individuals in a context sufficient to support BS2.
BS3
No well-established functional study demonstrating a normal effect for this variant was identified.
BS4
No non-segregation evidence was identified for this variant.
BP1
Although BCORL1 loss of function appears relevant to disease, the available evidence does not establish that pathogenic missense variants are uncommon enough for BP1 to be applied confidently.
BP2
No phase data or second-variant context was identified to support BP2.
BP5
No alternate molecular explanation for the phenotype was provided, so BP5 was not assessed.
BP6
No reputable external benign classification was identified because the variant is absent from ClinVar.
N/A · 5
PVS1 · 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= 0.000247116; MAF= 0.02471%, 254/1027856 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00215117; MAF= 0.21512%, 80/37189 alleles, homozygotes = 0); grpmax FAF= 0.00177053.
v2.1
This variant is present in gnomAD v2.1 (AF= 8.32737e-05; MAF= 0.00833%, 10/120086 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000388387; MAF= 0.03884%, 4/10299 alleles, homozygotes = 0); grpmax FAF= 0.00043111.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.025%
· 254 / 1,027,856
0 hom · FAF 0.18%
0 hom · FAF 0.18%
African/African American 80 / 37,189 |
0.22% |
Admixed American 16 / 30,562 |
0.052% |
Ashkenazi Jewish 7 / 17,854 |
0.039% |
European (Finnish) 11 / 30,008 |
0.037% |
Remaining individuals 8 / 40,541 |
0.02% |
European (non-Finnish) 126 / 796,403 |
0.016% |
East Asian 3 / 24,400 |
0.012% |
South Asian 3 / 46,715 |
0.0064% |
+ 2 not observed (Amish, Middle Eastern)
gnomAD v2.1
0.0083%
· 10 / 120,086
0 hom · FAF 0.043%
0 hom · FAF 0.043%
African/African American 4 / 10,299 |
0.039% |
Remaining individuals 1 / 3,601 |
0.028% |
European (Finnish) 1 / 11,554 |
0.0087% |
European (non-Finnish) 3 / 47,260 |
0.0063% |
Admixed American 1 / 19,124 |
0.0052% |
+ 3 not observed (Ashkenazi Jewish, East Asian, South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.610016.
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; COSV54404421, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links