BCORL1 c.4642C>T, p.Arg1548Trp
NM_021946.4:c.4642C>T
Variant of Uncertain Significance (VUS)
This variant is classified as VUS due to only moderate support for rarity (PM2) and supporting benign computational evidence (BP4), with no additional evidence to reach a definitive benign or pathogenic classification.
ACMG/AMP Criteria Applied
PM2
BP4
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.4642C>T
Protein Change
R1548W
Location
Exon 10
(Exon 10 of 12)
5'Exon Structure (12 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1548 in gene BCORL1
Variant interpretation based on transcript NM_021946.4
Genome Browser
Loading genome browser...
HGVS InputNM_021946:c.4642C>T
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Global Frequency
0.0307%
Low Frequency
Highest in Population
South Asian
0.121%
Common
Global: 0.0307%
South Asian: 0.121%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 205063Alt: 63Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0307%, 63/205063 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.121%, 23/19062 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
1 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Likely benign (1 clinical laboratories).
Functional Impact
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 1548 in gene BCORL1
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.264
0.264
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damaging
Benign:
CADD: 4.34metasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: it is a missense change (R1548W), not a null variant. Therefore, this criterion is not applied because the variant type does not meet the requirement for a null effect.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no known pathogenic variant at residue R1548. Therefore, this criterion is not applied because there is no established pathogenic variant causing the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "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 de novo occurrence or parental testing. Therefore, this criterion is not applied because de novo status has not been established.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: no functional characterization studies available. Therefore, this criterion is not applied because functional impact has not been demonstrated experimentally.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls." The evidence for this variant shows: no case-control data or reports of enrichment in affected individuals. Therefore, this criterion is not applied because population-based case data are lacking.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation." The evidence for this variant shows: no data indicating R1548 lies in a known hotspot or critical domain. Therefore, this criterion is not applied due to lack of domain or hotspot evidence.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in population databases." The evidence for this variant shows: MAF=0.0307% in gnomAD, which is below 0.1% and essentially absent in most populations. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders." The evidence for this variant shows: no information on trans configuration with other variants. Therefore, this criterion is not applied due to lack of zygosity and phase data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: it is a missense substitution without protein length change. Therefore, this criterion is not applied because the variant does not alter protein length.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen." The evidence for this variant shows: no other pathogenic missense variants reported at residue R1548. Therefore, this criterion is not applied due to absence of known pathogenic variants at the same residue.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo or parental testing data. Therefore, this criterion is not applied because assumed de novo status is not documented.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied because family segregation data are unavailable.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "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: insufficient constraint or mutational mechanism data for BCORL1. Therefore, this criterion is not applied due to lack of gene-specific intolerance evidence.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence for this variant shows: in silico tools predominantly predict benign impact (REVEL=0.26, SpliceAI=0.02). Therefore, this criterion is not applied because computational evidence does not support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotypic or clinical data provided. Therefore, this criterion is not applied because phenotype specificity is unknown.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence." The evidence for this variant shows: ClinVar reports VUS and Likely benign but no authoritative pathogenic assertion. Therefore, this criterion is not applied due to absence of a credible pathogenic-only source.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (>5%)." The evidence for this variant shows: MAF=0.0307%, well below 5%. Therefore, this criterion is not applied because allele frequency does not exceed the BA1 threshold.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: allele frequency is low (0.0307%) and not inconsistent with a rare disorder. Therefore, this criterion is not applied because frequency does not surpass expected maximum.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a fully penetrant disorder." The evidence for this variant shows: no data on observation in healthy individuals. Therefore, this criterion is not applied because healthy adult observations are not documented.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied because no experimental benign functional data exist.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members." The evidence for this variant shows: no family segregation information. Therefore, this criterion is not applied because segregation data are unavailable.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease." The evidence for this variant shows: BCORL1 disease mechanism is not exclusively loss-of-function. Therefore, this criterion is not applied because gene-specific mechanism does not support benign missense.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant." The evidence for this variant shows: no cis/trans data with other variants. Therefore, this criterion is not applied due to lack of allelic configuration information.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function." The evidence for this variant shows: this is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied because variant type does not match.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: in silico predictors predominantly benign (REVEL=0.26, SpliceAI=0.02) with mixed results but overall no predicted impact. Therefore, this criterion is applied at Supporting strength because computational data favor benign.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no case reports with alternate diagnoses. Therefore, this criterion is not applied because case-level alternative molecular data are lacking.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without accessible evidence." The evidence for this variant shows: ClinVar records Likely benign but with evidence not accessible; however, standard practice discourages BP6 without clear provenance. Therefore, this criterion is not applied due to insufficient validation of the source.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing." The evidence for this variant shows: it is a missense, not synonymous. Therefore, this criterion is not applied because the variant is not synonymous.