About BCORL1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BCORL1 c.1111A>C, p.(Thr371Pro)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
254 / 1,027,856 alleles
gnomAD v4.1: 254 / 1,027,856 alleles. Recorded AF 0.000247116. Recorded homozygote count 0.
gnomAD 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.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54404421, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 5 not met · 17 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The BCORL1 NM_021946.4:c.1111A>C (NP_068765.3:p.(Thr371Pro)) variant has not been reported in ClinVar.
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.
Cancer Hotspots did not identify a statistically significant hotspot at Thr371, so available evidence does not support PM1.
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.
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.
No criteria match.
Met · 1
BP4 SupportingAvailable 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. Details ▾Hide ▴
Rule
BP4 requires multiple computational lines of evidence suggesting no impact on gene or gene product.
Evidence considered
- SpliceAI max delta score 0.00
- BayesDel score -0.610016
Still missing
- REVEL was not available for this variant.
Sources
spliceai ↗bayesdel
Not met · 5 · evaluated, threshold not reached
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. PM1 is therefore not supported. Details ▾Hide ▴
Rule
PM1 requires location in a mutational hotspot or a well-established critical functional domain without benign variation.
Evidence considered
- Cancer Hotspots found no hotspot row for BCORL1 T371
- OncoKB provided only gene-level context
Still missing
- A curated domain-level source showing Thr371 lies in a critical region without benign variation would be needed.
Sources
PM2 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 non-VCEP PM2 rarity threshold of 0.1%, so PM2 is not met. Details ▾Hide ▴
Rule
For non-VCEP review, PM2 is considered only when population frequency remains below 0.1%.
Evidence considered
- gnomAD v2.1 total AF 0.00833%
- gnomAD v4.1 total AF 0.02471%
- gnomAD v4.1 highest observed population AF 0.21512% in African/African American samples
Sources
PP3 Available 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, which does not support a deleterious computational call. PP3 is therefore not met. Details ▾Hide ▴
Rule
PP3 requires multiple computational lines of evidence supporting a deleterious effect.
Evidence considered
- SpliceAI max delta score 0.00
- BayesDel score -0.610016
- REVEL not available
Still missing
- A validated damaging computational signal such as a strong missense predictor result would be needed.
Sources
spliceai ↗bayesdel
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. Details ▾Hide ▴
Rule
For non-VCEP review, BA1 is considered when population frequency exceeds 1%.
Evidence considered
- gnomAD v4.1 highest observed population AF 0.21512%
Sources
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. Details ▾Hide ▴
Rule
For non-VCEP review, BS1 is considered when population frequency exceeds 0.3%.
Evidence considered
- gnomAD v4.1 highest observed population AF 0.21512%
Sources
Not assessed · 17 · no assessment recorded
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. Details ▾Hide ▴
Rule
PS1 requires a previously established pathogenic or likely pathogenic variant with the same amino acid change.
Evidence considered
- ClinVar shows no entry for this variant
- No same-residue comparator variants were harvested
Still missing
- A confirmed pathogenic or likely pathogenic comparator causing the same amino acid substitution would be needed.
Sources
clinvar ↗pm5_candidates
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant. Details ▾Hide ▴
Rule
PS2 requires a de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed.
Evidence considered
- ClinVar has no submission for this variant
Still missing
- A published or submitted de novo observation with confirmed parentage would be needed.
Sources
PS3 No well-established functional study demonstrating a damaging effect for this specific variant was identified. Available curated review did not provide variant-specific functional evidence. Details ▾Hide ▴
Rule
PS3 requires well-established in vitro or in vivo functional studies supportive of a damaging effect.
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- A validated functional assay for p.(Thr371Pro) would be needed.
Sources
PS4 No enrichment in affected individuals, case series, or multiple independent germline observations was identified for this variant. The variant is absent from ClinVar, and available evidence does not establish increased prevalence in affected individuals over controls. Details ▾Hide ▴
Rule
PS4 requires significantly increased prevalence in affected individuals compared with controls.
Evidence considered
- ClinVar has no entry for this variant
Still missing
- Exact affected case counts and appropriate comparison data would be needed.
Sources
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. PM5 is therefore not assessed from the current evidence. Details ▾Hide ▴
Rule
PM5 requires a different pathogenic missense change at the same amino acid residue under an applicable same-residue framework.
Evidence considered
- PM5 candidate review found no comparator variants
- ClinVar has no entry for this variant
Still missing
- A confirmed pathogenic or likely pathogenic missense variant at the same residue under an applicable PM5 framework would be needed.
Sources
pm5_candidatesclinvar ↗
PM6 No presumed de novo observation without full parentage confirmation was identified for this variant. Details ▾Hide ▴
Rule
PM6 requires a de novo occurrence without confirmation of maternity and paternity.
Evidence considered
- ClinVar has no submission for this variant
Still missing
- A de novo report lacking full parentage confirmation would be needed.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
PP1 requires cosegregation with disease in multiple affected family members.
Evidence considered
- No ClinVar submissions or family evidence were available
Still missing
- Informative family segregation data would be needed.
Sources
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. Details ▾Hide ▴
Rule
PP2 requires a missense variant in a gene with low benign missense variation and where missense is a common disease mechanism.
Evidence considered
- Gene-level evidence supports loss of function
- but does not by itself establish PP2 conditions
Still missing
- Gene-level missense constraint or disease-mechanism evidence specific to PP2 would be needed.
Sources
pvs1_gene_contextPMID:30941876 ↗
PP4 No individual-level phenotype information was available to determine whether the clinical presentation is highly specific for a BCORL1-related disorder. Details ▾Hide ▴
Rule
PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology.
Evidence considered
- No phenotype-specific case data were provided
Still missing
- Detailed phenotype information and case-level correlation would be needed.
PP5 No reputable clinical source classification for this variant was identified because the variant is absent from ClinVar. Details ▾Hide ▴
Rule
PP5 requires a pathogenic assertion from a reputable source; use is limited and not established here.
Evidence considered
- ClinVar has no entry for this variant
Still missing
- A reputable external classification would be needed.
Sources
BS2 No evidence was identified showing this variant in unaffected individuals in a context sufficient to support BS2. Details ▾Hide ▴
Rule
BS2 requires observation in healthy adults for a disorder expected to be fully penetrant at an early age.
Evidence considered
- No unaffected-carrier evidence was available
Still missing
- Well-phenotyped unaffected carrier data would be needed.
BS3 No well-established functional study demonstrating a normal effect for this variant was identified. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect.
Evidence considered
- No variant-specific reviewed functional evidence was identified
Still missing
- A validated functional assay showing preserved BCORL1 function would be needed.
Sources
BS4 No non-segregation evidence was identified for this variant. Details ▾Hide ▴
Rule
BS4 requires lack of segregation in affected family members.
Evidence considered
- No family non-segregation data were available
Still missing
- Informative family data showing lack of segregation with disease would be needed.
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. Details ▾Hide ▴
Rule
BP1 applies to a missense variant in a gene where truncating variants are primarily known to cause disease.
Evidence considered
- Gene-level loss-of-function mechanism support alone is insufficient for BP1
Still missing
- Gene-level evidence showing disease is caused primarily by truncating variants with few pathogenic missense variants would be needed.
Sources
pvs1_gene_contextPMID:30941876 ↗
BP2 No phase data or second-variant context was identified to support BP2. Details ▾Hide ▴
Rule
BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant.
Evidence considered
- No phase or second-variant evidence was available
Still missing
- Phase information with another pathogenic variant would be needed.
BP5 No alternate molecular explanation for the phenotype was provided, so BP5 was not assessed. Details ▾Hide ▴
Rule
BP5 applies when the variant is found in a case with an alternate molecular basis for disease.
Evidence considered
- No alternate diagnostic explanation was available
Still missing
- A clearly established alternate cause of the phenotype would be needed.
BP6 No reputable external benign classification was identified because the variant is absent from ClinVar. Details ▾Hide ▴
Rule
BP6 requires a benign assertion from a reputable source; use is limited and not established here.
Evidence considered
- ClinVar has no entry for this variant
Still missing
- A reputable benign assertion would be needed.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ABCORL1 loss of function appears to be an established disease mechanism, but this variant is a missense substitution, NP_068765.3:p.(Thr371Pro), rather than a nonsense, frameshift, or canonical ±1/2 splice variant. The generic PVS1 framework therefore does not apply. Details ▾Hide ▴
Rule
Generic PVS1 is reserved for qualifying predicted loss-of-function variant classes when loss of function is an established mechanism.
Evidence considered
- BCORL1 gene-level loss-of-function mechanism supported
- Variant is missense p.(Thr371Pro)
- Generic PVS1 scaffold indicates PVS1 should not be applied
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMID:30941876 ↗PMID:38621993 ↗PMID:37904876 ↗PMID:38988263 ↗
PM3 N/APM3 is a recessive-phase criterion, and no recessive biallelic context was identified for this X-linked BCORL1 missense variant. Details ▾Hide ▴
Rule
PM3 applies to recessive disorders with detected variants in trans.
Evidence considered
- No biallelic recessive evidence was identified
PM4 N/AThis variant is a missense substitution and does not change protein length, so PM4 does not apply. Details ▾Hide ▴
Rule
PM4 applies to protein length changes from in-frame insertions/deletions or stop-loss variants.
Evidence considered
- Variant is p.(Thr371Pro) missense
BP3 N/AThis variant is a single amino acid substitution and not an in-frame insertion or deletion in a repetitive region, so BP3 does not apply. Details ▾Hide ▴
Rule
BP3 applies to in-frame deletions or insertions in repetitive regions without known function.
Evidence considered
- Variant is p.(Thr371Pro) missense
BP7 N/ABP7 is not applicable because this variant is missense rather than synonymous or deep intronic, even though SpliceAI predicts no significant splice effect. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain noncoding variants with no predicted splice impact and no conservation concern.
Evidence considered
- Variant is missense
- SpliceAI max delta score 0.00
Sources
Identifiers
- Gene
- BCORL1
- Transcript
- NM_021946.4
- Coding (HGVS c.)
- NM_021946.4:c.1111A>C
- Protein (HGVS p.)
- NP_068765.3:p.(Thr371Pro)
- GRCh38
- chrX:130013883 A>C
- GRCh37
- chrX:129147859 A>C
- COSMIC
- COSV54404421
Gene diagram
Every interpreted variant in BCORL1, mapped onto the exon structure of NM_021946.4. Select a row to find it on the plot.
BCORL1NM_021946.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BCORL1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
254 / 1,027,856 alleles
AF 0.000247 · 0 homozygotes · FAF 0.00177
gnomAD v2.1
10 / 120,086 alleles
AF 8.33e-05 · 0 homozygotes · FAF 0.000431
By genetic ancestry
gnomAD v4.1
AF 0.00025 · 254 / 1,027,856 alleles · 0 hom · FAF 0.0018
| African/African American80 / 37,189 | 0.0022 |
| Admixed American16 / 30,562 | 0.00052 |
| Ashkenazi Jewish7 / 17,854 | 0.00039 |
| European (Finnish)11 / 30,008 | 0.00037 |
| Remaining individuals8 / 40,541 | 0.0002 |
| European (non-Finnish)126 / 796,403 | 0.00016 |
| East Asian3 / 24,400 | 0.00012 |
| South Asian3 / 46,715 | 6.4e-05 |
0 alternate alleles recorded in 2 other groups: Amish, Middle Eastern.
gnomAD v2.1
AF 8.3e-05 · 10 / 120,086 alleles · 0 hom · FAF 0.00043
| African/African American4 / 10,299 | 0.00039 |
| Remaining individuals1 / 3,601 | 0.00028 |
| European (Finnish)1 / 11,554 | 8.7e-05 |
| European (non-Finnish)3 / 47,260 | 6.3e-05 |
| Admixed American1 / 19,124 | 5.2e-05 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, South Asian.
Statements
gnomAD 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.
gnomAD 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.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- -0.610
How the predictions were used
BP4 SupportingAvailable 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. Details ▾Hide ▴
Rule
BP4 requires multiple computational lines of evidence suggesting no impact on gene or gene product.
Evidence considered
- SpliceAI max delta score 0.00
- BayesDel score -0.610016
Still missing
- REVEL was not available for this variant.
Sources
spliceai ↗bayesdel
PP3 Available 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, which does not support a deleterious computational call. PP3 is therefore not met. Details ▾Hide ▴
Rule
PP3 requires multiple computational lines of evidence supporting a deleterious effect.
Evidence considered
- SpliceAI max delta score 0.00
- BayesDel score -0.610016
- REVEL not available
Still missing
- A validated damaging computational signal such as a strong missense predictor result would be needed.
Sources
spliceai ↗bayesdel
BP7 N/ABP7 is not applicable because this variant is missense rather than synonymous or deep intronic, even though SpliceAI predicts no significant splice effect. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain noncoding variants with no predicted splice impact and no conservation concern.
Evidence considered
- Variant is missense
- SpliceAI max delta score 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.610016.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
254 / 1,027,856 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_021946.4%3Ac.1111A%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-129147859-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-130013883-A-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_021946.4%3Ac.1111…
- OncoKB ↗www.oncokb.org/gene/BCORL1/T371P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=162422257
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.610016.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54404421, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.