About BCORL1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BCORL1 c.3143G>A, p.(Arg1048Gln)
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present in gnomAD at extremely low frequency: v2.1 AF=0.019% (39/205,240 alleles), v4.1 AF=0.038% (464/1,210,072 alleles), grpmax FAF=0.045%. All frequencies are below the 0.1% PM2 threshold. Zero homozygotes observed in both datasets. Absent from gnomAD-Canada.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on gene product or splicing. BayesDel score is -0.289255 (benign range; damaging threshold approximately >+0.07). SpliceAI max delta score is 0.00 (no predicted splicing alteration). REVEL score is unavailable but the concordance of BayesDel and SpliceAI supports a benign computational profile.
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: PM2 supporting, BP4 supporting; combination = 1 supporting + 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
464 / 1,210,072 alleles
gnomAD v4.1: 464 / 1,210,072 alleles. Recorded AF 0.000383448. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000190021; MAF= 0.01900%, 39/205240 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000750047; MAF= 0.07500%, 4/5333 alleles, homozygotes = 0); grpmax FAF= 0.00022236.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV106354134, n = 1 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.
29 criteria with recorded statuses: 2 met · 20 not met · 1 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
BCORL1 c.3143G>A (p.Arg1048Gln) is a missense variant in exon 3 of this X-linked transcriptional corepressor gene.
This variant is present in gnomAD v4.1 at an overall allele frequency of 0.038% (464/1,210,072 alleles) and in v2.1 at 0.019% (39/205,240 alleles), with zero homozygotes observed (PM2_Supporting).
Multiple in silico tools predict a benign effect: BayesDel score -0.289255 is in the benign range, and SpliceAI predicts no splicing alteration (max delta 0.00) (BP4_Supporting).
No functional studies, de novo observations, case-control data, cosegregation evidence, or ClinVar classifications are available for this variant.
With one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting), the evidence is insufficient to classify this variant as either likely pathogenic or likely benign. This variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines (PMID:25741868).
No criteria match.
Met · 2
PM2 SupportingThis variant is present in gnomAD at extremely low frequency: v2.1 AF=0.019% (39/205,240 alleles), v4.1 AF=0.038% (464/1,210,072 alleles), grpmax FAF=0.045%. All frequencies are below the 0.1% PM2 threshold. Zero homozygotes observed in both datasets. Absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 39/205240 alleles (AF=0.019%). gnomAD v4.1: 464/1210072 alleles (AF=0.038%). Both below PM2 0.1% threshold. Zero homozygotes.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product or splicing. BayesDel score is -0.289255 (benign range; damaging threshold approximately >+0.07). SpliceAI max delta score is 0.00 (no predicted splicing alteration). REVEL score is unavailable but the concordance of BayesDel and SpliceAI supports a benign computational profile. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.289255 (benign). SpliceAI: max delta 0.00 (no splice impact).
Still missing
- REVEL score unavailable for cross-validation.
Sources
bayesdelspliceai ↗
Not met · 20 · evaluated, threshold not reached
PS2 No de novo observation has been reported for NM_021946.4:c.3143G>A in the available literature or databases. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar
- literature
- or database sources.
Still missing
- No family-based sequencing data available.
PS3 No well-established in vitro or in vivo functional studies demonstrate a damaging effect for this variant. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific functional evidence curated. COSMIC reports one somatic occurrence (COSV106354134) but this does not constitute functional validation of a damaging effect. Details ▾Hide ▴
Evidence considered
- OncoKB: no variant-specific functional evidence. COSMIC: one somatic occurrence without functional characterization.
Still missing
- No functional studies available for this variant.
Sources
PS4 No case-control studies or statistically significant enrichment of this variant in affected individuals versus controls has been reported. Details ▾Hide ▴
Evidence considered
- No case-control or burden data available.
Still missing
- No case-control data available for BCORL1 c.3143G>A.
PM1 This variant does not lie in a statistically significant somatic mutational hotspot, and there is no evidence that residue 1048 resides in a well-established critical functional domain where pathogenic missense variation clusters without benign variation. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue not significant. No domain-level constraint data specific to Arg1048.
Still missing
- No BCORL1 domain-specific constraint or functional domain map for missense variation.
PM5 No pathogenic or likely pathogenic missense variant at the same amino acid residue (Arg1048) with a different amino acid change was identified. Automated PM5 candidate search returned zero candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate search yielded no same-residue pathogenic comparators.
Sources
pm5_candidates
PM6 No de novo observation has been reported for this variant. PM6 requires a confirmed de novo occurrence with or without confirmed parentage. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- No trio or family-based sequencing data available.
PP1 No cosegregation data are available for this variant in affected families. Details ▾Hide ▴
Evidence considered
- No family cosegregation data identified.
Still missing
- No pedigree or linkage data available.
PP3 In silico tools do not support a damaging effect. BayesDel score is -0.289255, which falls in the benign range (damaging threshold approximately >+0.07). SpliceAI max delta score is 0.00, predicting no splicing alteration. REVEL score is unavailable. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.289255 (benign range). SpliceAI max delta: 0.00 (no splice impact). REVEL: not available.
Still missing
- REVEL score unavailable for chrX variant.
Sources
bayesdelspliceai ↗
PP4 No patient phenotype or family history information is available for the individual carrying this variant. PP4 requires the variant to be identified in a patient whose phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available.
Still missing
- No proband phenotype or family history provided.
PP5 This variant has not been reported as pathogenic by a reputable source. It is absent from ClinVar and has not been classified by any clinical laboratory or expert panel. Details ▾Hide ▴
BA1 Allele frequency in gnomAD v4.1 is 0.038% (464/1,210,072 alleles), well below the 1% BA1 threshold. The highest subpopulation frequency (European non-Finnish) is 0.048%, also below 1%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 overall AF=0.038%
- max subpop AF=0.048% — both below 1%.
Sources
BS1 Allele frequency in gnomAD v4.1 is 0.038% (464/1,210,072 alleles), below the 0.3% BS1 threshold. The grpmax FAF is 0.045%, also below 0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 overall AF=0.038%
- grpmax FAF=0.045% — both below 0.3%.
Sources
BS2 Although the variant is observed in 464 alleles in gnomAD v4.1, a population database enriched for ostensibly healthy individuals, specific evidence confirming that hemizygous male carriers are unaffected is not available. For an X-linked gene such as BCORL1, BS2 requires observation in a healthy hemizygous adult; carrier sex breakdown and individual-level phenotype data are absent. Details ▾Hide ▴
Evidence considered
- Observed in 464 alleles in gnomAD v4.1
- but carrier sex and phenotype data unavailable.
Still missing
- No carrier-level sex or phenotype data to confirm healthy hemizygous status.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate no damaging effect on protein function or splicing for this variant. OncoKB does not curate benign functional evidence. Details ▾Hide ▴
Evidence considered
- No functional studies showing no damaging effect identified.
Still missing
- No functional data of any kind available for this variant.
Sources
BS4 No non-segregation data are available for this variant in affected families. Details ▾Hide ▴
Evidence considered
- No family non-segregation data identified.
Still missing
- No pedigree data available.
BP1 BCORL1 missense variants have been established as a disease mechanism. Germline missense variants in BCORL1 are associated with an X-linked syndrome of intellectual disability, dysmorphic features, and behavioral abnormalities (PMID:30941876). BP1 is only applicable when the primary disease mechanism for a gene is truncating variants. Details ▾Hide ▴
Evidence considered
- PMID:30941876 reports BCORL1 missense variants as a disease mechanism for X-linked intellectual disability syndrome.
BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant in BCORL1. BCORL1 is X-linked; BP2 would generally apply to recessive disorders. Details ▾Hide ▴
Evidence considered
- X-linked gene
- no trans configuration data applicable or available.
BP5 No case has been reported in which this variant is present alongside an alternate molecular basis for disease. BP5 requires observation of the variant in a case with an alternate established genetic cause. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
Still missing
- No case-level genetic data available.
BP6 This variant has not been reported as benign by a reputable source. It is absent from ClinVar and has not been classified by any clinical laboratory or expert panel. Details ▾Hide ▴
PS5 This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source or clinical laboratory. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no pathogenic classification by any submitter.
Sources
Not assessed · 1 · no assessment recorded
PP2 Insufficient gene-level constraint data to determine whether BCORL1 has a low rate of benign missense variation. No HCI prior probability, REVEL score, or gnomAD missense Z-score is available for this gene. BCORL1 is X-linked and associated with an X-linked intellectual disability syndrome; however, without quantitative constraint metrics, the PP2 threshold cannot be evaluated. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported. REVEL: not found. No gnomAD missense constraint metrics available.
Still missing
- Gene-level missense constraint metrics (Z-score
- pLI
- missense OE ratio) unavailable for BCORL1.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.3143G>A, p.Arg1048Gln) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 decision tree (PMC6185798), PVS1 is not applicable. Details ▾Hide ▴
PS1 N/ANo known pathogenic variant at the same amino acid position (Arg1048) with a different nucleotide change is present in ClinVar. PS1 requires an established pathogenic comparator at the same residue. Details ▾Hide ▴
Evidence considered
- No ClinVar entries at residue 1048 with a pathogenic or likely pathogenic classification.
Sources
PM3 N/APM3 applies to recessive disorders where a variant is detected in trans with a pathogenic variant. BCORL1 is X-linked; recessive trans configuration is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein-length-altering variants (in-frame deletions/insertions, stop-loss). This is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions without known function. This is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 is only applicable to synonymous (silent) variants with no predicted splicing impact. This variant is a missense substitution (c.3143G>A, p.Arg1048Gln). Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
Identifiers
- Gene
- BCORL1
- Transcript
- NM_021946.4
- Coding (HGVS c.)
- NM_021946.4:c.3143G>A
- Protein (HGVS p.)
- NP_068765.3:p.(Arg1048Gln)
- GRCh38
- chrX:130015915 G>A
- GRCh37
- chrX:129149891 G>A
- COSMIC
- COSV106354134
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
464 / 1,210,072 alleles
AF 0.000383 · 0 homozygotes · FAF 0.000446
gnomAD v2.1
39 / 205,240 alleles
AF 0.00019 · 0 homozygotes · FAF 0.000222
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00038 · 464 / 1,210,072 alleles · 0 hom · FAF 0.00045
| European (non-Finnish)433 / 895,300 | 0.00048 |
| Remaining individuals17 / 47,604 | 0.00036 |
| European (Finnish)7 / 46,506 | 0.00015 |
| Admixed American5 / 45,744 | 0.00011 |
| South Asian1 / 56,867 | 1.8e-05 |
| African/African American1 / 57,189 | 1.7e-05 |
0 alternate alleles recorded in 4 other groups: Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00019 · 39 / 205,240 alleles · 0 hom · FAF 0.00022
| Remaining individuals4 / 5,333 | 0.00075 |
| European (non-Finnish)27 / 92,592 | 0.00029 |
| European (Finnish)3 / 18,629 | 0.00016 |
| Admixed American4 / 28,054 | 0.00014 |
| South Asian1 / 19,080 | 5.2e-05 |
0 alternate alleles recorded in 3 other groups: African/African American, Ashkenazi Jewish, East Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000383448; MAF= 0.03834%, 464/1210072 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000483637; MAF= 0.04836%, 433/895300 alleles, homozygotes = 0); grpmax FAF= 0.0004457.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000190021; MAF= 0.01900%, 39/205240 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000750047; MAF= 0.07500%, 4/5333 alleles, homozygotes = 0); grpmax FAF= 0.00022236.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- -0.289
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product or splicing. BayesDel score is -0.289255 (benign range; damaging threshold approximately >+0.07). SpliceAI max delta score is 0.00 (no predicted splicing alteration). REVEL score is unavailable but the concordance of BayesDel and SpliceAI supports a benign computational profile. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.289255 (benign). SpliceAI: max delta 0.00 (no splice impact).
Still missing
- REVEL score unavailable for cross-validation.
Sources
bayesdelspliceai ↗
PP3 In silico tools do not support a damaging effect. BayesDel score is -0.289255, which falls in the benign range (damaging threshold approximately >+0.07). SpliceAI max delta score is 0.00, predicting no splicing alteration. REVEL score is unavailable. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.289255 (benign range). SpliceAI max delta: 0.00 (no splice impact). REVEL: not available.
Still missing
- REVEL score unavailable for chrX variant.
Sources
bayesdelspliceai ↗
BP7 N/ABP7 is only applicable to synonymous (silent) variants with no predicted splicing impact. This variant is a missense substitution (c.3143G>A, p.Arg1048Gln). Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.289255.
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
464 / 1,210,072 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.3143G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-129149891-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-130015915-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/X-130015915-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_021946.4%3Ac.3143…
- OncoKB ↗www.oncokb.org/gene/BCORL1/R1048Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=193266705
- 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= 0.000383448; MAF= 0.03834%, 464/1210072 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000483637; MAF= 0.04836%, 433/895300 alleles, homozygotes = 0); grpmax FAF= 0.0004457.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000190021; MAF= 0.01900%, 39/205240 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000750047; MAF= 0.07500%, 4/5333 alleles, homozygotes = 0); grpmax FAF= 0.00022236.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
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 = -0.289255.
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; COSV106354134, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.