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
BCORL1
Final classification
VUS
BCORL1 c.1111A>C · p.Thr371Pro
BCORL1
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 ↗
Gene diagram
· NM_021946.4 · variants mapped to exon structure
BCORL1
NM_021946.4
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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