BCORL1 c.5042dup, p.Gly1682ArgfsTer4
NM_021946.4:c.5042dup
COSM4615384
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
17 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
BCORL1
Transcript
NM_021946.4
Total Exons
12
Strand
Forward (+)
Reference Sequence
NC_000023.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_021946.2 | Alternative | 13 exons | Forward |
| NM_021946.5 | Alternative | 13 exons | Forward |
| NM_021946.3 | Alternative | 13 exons | Forward |
Variant Details
HGVS Notation
NM_021946.4:c.5042dup
Protein Change
G1682Rfs*4
Location
Exon 12
(Exon 12 of 12)
5'
Exon Structure (12 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1682 in gene BCORL1
Alternate Identifiers
COSM4615384
Variant interpretation based on transcript NM_021946.4
Clinical Evidence
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 182522
Alt: 0
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0%, 0/182522 alleles, homozygotes = 0) but does not appear at a higher frequency in any of the selected populations. The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications
0 publications
Clinical Statement
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 1682 in gene BCORL1
Functional Studies
Summary
The BCORL1 G1682Rfs*4 variant is a truncating mutation that results in the loss of the nuclear receptor recruitment motif and the C-terminus of the protein. Functional evidence indicates that such truncating mutations in BCORL1 disrupt its role as a transcriptional co-repressor, which is involved in the repression of E-cadherin through interactions with class II histone deacetylases and CTBP1. This disruption supports a damaging effect, consistent with its identification in hematopoietic malignancies and its proposed role as a tumor suppressor.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: 'PVS1 – Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion in a LoF gene)'. The evidence for this variant shows: c.5042dupC causes a frameshift (G1682Rfs*4) leading to premature truncation and loss of critical C-terminal domains in BCORL1, a gene with established LoF disease mechanism. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a gene where LoF is a known mechanism of disease.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: G1682Rfs*4 is a frameshift, not a missense change matching any known pathogenic amino acid substitution. Therefore, this criterion is not applied at Not Applied strength because the variant does not produce the same amino acid change as any known pathogenic variant.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no information on parental testing or de novo status is available. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be confirmed.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: in vitro studies demonstrate truncation removes the nuclear receptor recruitment motif and disrupts BCORL1 co-repressor function, consistent with damaging effect. Therefore, this criterion is applied at Strong strength because well-established functional studies support a damaging effect.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'PS4 – Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case–control or cohort frequency data demonstrating enrichment in affected individuals. Therefore, this criterion is not applied at Not Applied strength because comparative prevalence data are lacking.
PM1
PM1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'PM1 – Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: no specific hotspot or well-established functional domain annotation for c.5042dupC. Therefore, this criterion is not applied at Not Applied strength because the variant is not in a defined hotspot or critical domain.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'PM2 – Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: MAF=0% in gnomAD (0/182,522 alleles). Therefore, this criterion is applied at Moderate strength because the variant is absent from large population databases.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'PM3 – Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: no evidence of recessive inheritance or trans configuration with another pathogenic allele. Therefore, this criterion is not applied at Not Applied strength because relevant trans data are not available.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: it is a frameshift leading to truncation, not an in-frame indel or stop-loss. Therefore, this criterion is not applied at Not Applied strength because the variant type does not meet PM4.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: it is a frameshift, not a novel missense change at an existing pathogenic residue. Therefore, this criterion is not applied at Not Applied strength.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'PM6 – Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo or parental data provided. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be assumed.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'PP1 – Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength because co-segregation data are not available.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'PP2 – Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied at Not Applied strength.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)'. The evidence for this variant shows: in silico tools (SpliceAI, others) do not predict deleterious effects. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support pathogenicity.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'PP4 – Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no detailed phenotype/family history data. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity cannot be assessed.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'PP5 – Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: no external reputable pathogenic assertion found. Therefore, this criterion is not applied at Not Applied strength.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'BA1 – Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows: MAF=0% in gnomAD, not exceeding any threshold. Therefore, this criterion is not applied at Not Applied strength.
BS1
BS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'BS1 – Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: MAF=0% in population databases. Therefore, this criterion is not applied at Not Applied strength.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'BS2 – Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: no data on occurrence in healthy individuals. Therefore, this criterion is not applied at Not Applied strength.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'BS3 – Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied at Not Applied strength.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'BS4 – Lack of segregation in affected family members'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'BP1 – Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: it is a frameshift leading to LoF, not a missense. Therefore, this criterion is not applied at Not Applied strength.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no data on cis/trans configuration with other variants. Therefore, this criterion is not applied at Not Applied strength.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'BP3 – In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: it is a frameshift, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'BP4 – Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: SpliceAI and other in silico tools predict no impact on splicing or function. Therefore, this criterion is applied at Supporting strength because computational evidence supports a benign effect.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'BP5 – Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied at Not Applied strength.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'BP6 – Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: no reputable benign assertion found. Therefore, this criterion is not applied at Not Applied strength.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'BP7 – Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is a frameshift, not synonymous. Therefore, this criterion is not applied at Not Applied strength.