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BCORL1c.4642C>TUncertain significance
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Variant interpretation report

BCORL1 c.4642C>T, p.(Arg1548Trp)

NM_021946.4:c.4642C>T NP_068765.3:p.(Arg1548Trp) View identifiers
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.

About BCORL1

No gene-level summary was recorded for this case.

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

Present in gnomAD at very low frequency: v2.1 overall AF=0.03072% (63/205,063 alleles) and v4.1 overall AF=0.03812% (461/1,209,451 alleles), both below the 0.1% PM2 threshold. No homozygotes observed. SAS subpopulation AF in v2.1 (0.12%) slightly exceeds threshold but grpmax FAF (0.082%) is below 0.1%.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no damaging effect: BayesDel score 0.00572 predicts a benign impact, and SpliceAI max delta 0.02 predicts no splicing alteration.

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 benign; 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
461 / 1,209,451 alleles

gnomAD v4.1: 461 / 1,209,451 alleles. Recorded AF 0.000381165. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000307223; MAF= 0.03072%, 63/205063 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00120659; MAF= 0.12066%, 23/19062 alleles, homozygotes = 0); grpmax FAF= 0.00082459.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.000829646017699115, 12/14464 alleles, homozygotes = 0).

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

1 Uncertain significance · 1 Likely benign. ClinVar API review status: criteria provided, single submitter.

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; COSV113432302, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
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.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_021946.4:c.4642C>T (p.Arg1548Trp) is a missense variant in BCORL1, a transcriptional corepressor located on chromosome Xq26.1.

This variant is present in gnomAD at very low frequency: v2.1 overall AF=0.03072% (63/205,063 alleles) and v4.1 overall AF=0.03812% (461/1,209,451 alleles), meeting PM2 at supporting level (PM2_Supporting). No homozygotes have been observed.

Multiple in silico tools predict a benign effect: BayesDel score 0.00572 is strongly benign-leaning and SpliceAI max delta 0.02 predicts no splicing impact, meeting BP4 at supporting benign level (BP4_Supporting).

The variant has been reported in ClinVar as Uncertain significance (Ambry Genetics, criteria provided, single submitter) and Likely benign (PreventionGenetics, no assertion criteria). No expert panel review is available. Neither PP5 nor BP6 criteria are met.

No variant-specific functional data, de novo reports, case-control studies, cosegregation data, or publications mentioning this exact variant were identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence.

The combined criteria yield 1 supporting pathogenic (PM2_Supporting) and 1 supporting benign (BP4_Supporting), which are balanced. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868), the final classification is Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingPresent in gnomAD at very low frequency: v2.1 overall AF=0.03072% (63/205,063 alleles) and v4.1 overall AF=0.03812% (461/1,209,451 alleles), both below the 0.1% PM2 threshold. No homozygotes observed. SAS subpopulation AF in v2.1 (0.12%) slightly exceeds threshold but grpmax FAF (0.082%) is below 0.1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=0.03072%
  • 63/205063 alleles
  • 0 homozygotes.
  • gnomAD v4.1: AF=0.03812%
  • 461/1209451 alleles
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple lines of computational evidence suggest no damaging effect: BayesDel score 0.00572 predicts a benign impact, and SpliceAI max delta 0.02 predicts no splicing alteration. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.00572 (benign prediction).
  • SpliceAI: max delta 0.02 (no predicted splicing impact).
Still missing
  • REVEL score unavailable for chrX.
Sources
bayesdelspliceai ↗

Not met · 20 · evaluated, threshold not reached

PS1 No evidence of a different nucleotide change at residue 1548 resulting in an established pathogenic variant. Details ▾Hide ▴
Still missing
  • No same-residue pathogenic comparator identified.
PS2 No de novo occurrence data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing data or family studies available.
PS3 No variant-specific functional data available. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. BayesDel score (0.00572) is benign-leaning. No publications identified with functional characterization of this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence.
  • BayesDel: 0.00572 (benign-leaning).
Still missing
  • No experimental functional studies for NM_021946.4:c.4642C>T identified.
Sources
oncokb ↗bayesdel
PS4 No case-control or statistical enrichment data available for this variant. Details ▾Hide ▴
Still missing
  • No case-control studies available.
PM1 Residue 1548 is not in a statistically significant cancer hotspot per cancerhotspots.org. No domain-level functional evidence specific to this residue was identified in the available data. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org: residue not significant
  • exact variant not listed.
Still missing
  • No domain-level functional characterization of residue Arg1548 in BCORL1.
PM5 No pathogenic missense variant identified at the same residue (Arg1548) to serve as a comparator for PM5. Automated candidate harvesting found no same-residue pathogenic variants in ClinVar. Details ▾Hide ▴
Evidence considered
  • No pathogenic same-residue comparator identified.
Still missing
  • No pathogenic R1548 variant identified in ClinVar.
PM6 No de novo occurrence data available; paternity not confirmed. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PP1 No cosegregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family studies or cosegregation data.
PP3 In silico tools do not support a damaging effect: BayesDel score 0.00572 is strongly benign-leaning, SpliceAI max delta 0.02 predicts no splicing impact, and REVEL is unavailable. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.00572 (benign).
  • SpliceAI: max delta 0.02 (no predicted splice impact).
Still missing
  • REVEL score unavailable for chrX variants.
Sources
bayesdelspliceai ↗
PP4 No specific patient phenotype data available for comparison with BCORL1-related disorder spectrum. Details ▾Hide ▴
Still missing
  • No phenotype data available for the tested individual.
PP5 ClinVar review status is 'criteria provided, single submitter' (not 3-star expert panel). No expert panel classification as pathogenic. One submitter classified as VUS, another as Likely benign without assertion criteria. Details ▾Hide ▴
Evidence considered
  • ClinVar: 1 VUS (Ambry Genetics)
  • 1 Likely benign (PreventionGenetics
  • no criteria). No expert panel review.
Still missing
  • No 3-star expert panel classification available.
Sources
clinvar ↗
BA1 Overall allele frequency in gnomAD (v2.1: 0.03072%, v4.1: 0.03812%) is well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=0.03%.
  • gnomAD v4.1: AF=0.04%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Overall allele frequency in gnomAD (v2.1: 0.03072%, v4.1: 0.03812%) is well below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD overall AF well below 0.3%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data on observation of this variant in healthy adults beyond gnomAD population data. BCORL1 is X-linked with age-related penetrance considerations; observation in healthy adults is not well characterized. Details ▾Hide ▴
Still missing
  • No dedicated healthy cohort data for BCORL1.
BS3 No well-established functional studies demonstrating no damaging effect for this variant. No variant-specific functional data identified. Details ▾Hide ▴
Still missing
  • No functional studies identified for NM_021946.4:c.4642C>T.
BS4 No nonsegregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family studies showing lack of segregation with disease.
BP1 While BCORL1 loss-of-function is a supported disease mechanism, germline missense variants in BCORL1 have been reported as pathogenic (PMID:30941876, Shukla et al. 2019), demonstrating that missense is also a disease mechanism. BP1 requires that the disease mechanism is exclusively truncating. Details ▾Hide ▴
Evidence considered
  • Shukla et al. 2019 (PMID:30941876) reported pathogenic germline BCORL1 missense variants associated with intellectual disability.
BP5 No alternate molecular basis for disease has been identified in a case harboring this variant. Details ▾Hide ▴
Still missing
  • No alternate molecular cause identified.
BP6 ClinVar review status is 'criteria provided, single submitter' (not 3-star expert panel). No expert panel classification as benign or likely benign with 3-star review status. Details ▾Hide ▴
Evidence considered
  • ClinVar: no 3-star expert panel classification available.
Still missing
  • No expert panel benign classification.
Sources
clinvar ↗
PS5 No reputable source reports this variant as pathogenic. ClinVar classifications are Uncertain significance (Ambry Genetics, criteria provided) and Likely benign (PreventionGenetics, no assertion criteria). Details ▾Hide ▴
Evidence considered
  • ClinVar: VUS (1 submitter) and Likely benign (1 submitter
  • no criteria).
Still missing
  • No expert panel or multi-submitter pathogenic classification.
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

PP2 Missense constraint (z-score) data for BCORL1 was not available in the evidence files. Cannot determine whether BCORL1 has a low rate of benign missense variation. Details ▾Hide ▴
Still missing
  • gnomAD missense constraint metrics (z-score
  • o/e) for BCORL1 not available.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution (p.Arg1548Trp) is not a null variant; PVS1 framework (PMC6185798) does not apply to missense variants. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not a nonsense
  • frameshift
  • or canonical splice-site variant.
Sources
pvs1_generic_framework ↗
PM3 N/ABCORL1 is X-linked; PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis is a missense substitution; PM4 applies to non-repeat in-frame deletions/insertions and stop-loss variants. Details ▾Hide ▴

No further detail was recorded.

BP2 N/ABCORL1 is located on chromosome X; BP2 (observed in trans with a dominant pathogenic variant) does not apply to X-linked genes. Details ▾Hide ▴
Evidence considered
  • X-linked gene
  • trans configuration not applicable.
BP3 N/AThis is a missense substitution; BP3 applies to in-frame deletions/insertions in repetitive regions. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (p.Arg1548Trp), not a synonymous variant with no predicted splicing impact. BP7 does not apply to missense substitutions. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 applies to synonymous variants and intronic variants outside splice sites.

Identifiers

Gene
BCORL1
Transcript
NM_021946.4
Coding (HGVS c.)
NM_021946.4:c.4642C>T
Protein (HGVS p.)
NP_068765.3:p.(Arg1548Trp)
GRCh38
chrX:130050740 C>T
GRCh37
chrX:129184715 C>T
ClinVar
3047703
COSMIC
COSV113432302

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…
gnomAD v4.1 461 / 1,209,451 alleles AF 0.000381 · 0 homozygotes · FAF 0.0005
gnomAD v2.1 63 / 205,063 alleles AF 0.000307 · 0 homozygotes · FAF 0.000825
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00038 · 461 / 1,209,451 alleles · 0 hom · FAF 0.0005
South Asian38 / 56,798 0.00067
European (non-Finnish)389 / 894,834 0.00043
Remaining individuals20 / 47,597 0.00042
African/African American11 / 57,151 0.00019
Admixed American3 / 45,708 6.6e-05
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.

gnomAD v2.1

AF 0.00031 · 63 / 205,063 alleles · 0 hom · FAF 0.00082
South Asian23 / 19,062 0.0012
Remaining individuals5 / 5,328 0.00094
European (non-Finnish)30 / 92,512 0.00032
African/African American3 / 19,021 0.00016
Admixed American2 / 28,033 7.1e-05
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, European (Finnish).

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000381165; MAF= 0.03812%, 461/1209451 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000669038; MAF= 0.06690%, 38/56798 alleles, homozygotes = 0); grpmax FAF= 0.00050041.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000307223; MAF= 0.03072%, 63/205063 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00120659; MAF= 0.12066%, 23/19062 alleles, homozygotes = 0); grpmax FAF= 0.00082459.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.000829646017699115, 12/14464 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -23 bp
0.020
SpliceAI acceptor gainat -103 bp
0.000
SpliceAI donor lossat +54 bp
0.020
SpliceAI donor gainat +65 bp
0.000
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
0.006

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no damaging effect: BayesDel score 0.00572 predicts a benign impact, and SpliceAI max delta 0.02 predicts no splicing alteration. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.00572 (benign prediction).
  • SpliceAI: max delta 0.02 (no predicted splicing impact).
Still missing
  • REVEL score unavailable for chrX.
Sources
bayesdelspliceai ↗
PP3 In silico tools do not support a damaging effect: BayesDel score 0.00572 is strongly benign-leaning, SpliceAI max delta 0.02 predicts no splicing impact, and REVEL is unavailable. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.00572 (benign).
  • SpliceAI: max delta 0.02 (no predicted splice impact).
Still missing
  • REVEL score unavailable for chrX variants.
Sources
bayesdelspliceai ↗
BP7 N/AThis is a missense variant (p.Arg1548Trp), not a synonymous variant with no predicted splicing impact. BP7 does not apply to missense substitutions. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 applies to synonymous variants and intronic variants outside splice sites.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.00572034.

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 v4.1 461 / 1,209,451 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar 1 Uncertain significance · 1 Likely benign 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

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= 0.000381165; MAF= 0.03812%, 461/1209451 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000669038; MAF= 0.06690%, 38/56798 alleles, homozygotes = 0); grpmax FAF= 0.00050041.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000307223; MAF= 0.03072%, 63/205063 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00120659; MAF= 0.12066%, 23/19062 alleles, homozygotes = 0); grpmax FAF= 0.00082459.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.000829646017699115, 12/14464 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 3047703)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.00572034.

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; COSV113432302, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.