Classification rationale

PM2 BP4 VUS

BCORL1 c.2361A>T

The BCORL1 c.2361A>T (p.Pro787=) variant has not been reported in ClinVar.¹ This variant is present in gnomAD at 0.00164% in v2.1 (3/183251 alleles; grpmax FAF 9.75e-06) and 0.00107% in v4.1 (13/1212241 alleles; grpmax FAF 8.1e-06), which is below the default non-VCEP PM2 threshold of 0.1%.² SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.00, arguing against a computationally predicted splice-disrupting effect.³

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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.

Gene diagram · NM_021946.4 · variants mapped to exon structure

BCORL1 NM_021946.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 18 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

This variant is present at very low frequency in population databases and remains below the default non-VCEP PM2 threshold of 0.1%. In gnomAD v2.1 the allele frequency is 0.00164% (3/183251; grpmax FAF 9.75e-06), and in gnomAD v4.1 the allele frequency is 0.00107% (13/1212241; grpmax FAF 8.1e-06).

gnomAD v2.1 AF 1.6371e-05gnomAD v4.1 AF 1.07239e-05

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

Available computational evidence supports no predicted molecular impact. This variant is synonymous at p.(Pro787=), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00.

Synonymous protein consequenceSpliceAI max delta score 0.00

spliceai ↗

Assessed · not applied · 4 not met · 14 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.

PS3 No well-established functional or RNA study demonstrating a damaging effect of this exact variant was identified.

PS4 No enrichment data in affected individuals versus controls were identified for this variant.

PM1 This variant does not lie in a statistically significant hotspot, and no evidence was identified that codon 787 is in a well-established critical functional region without benign variation.

PM6 No presumed de novo report was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a damaging effect.

PP4 No phenotype-specific clinical evidence was provided to show that the observed presentation is highly specific for BCORL1-related disease.

PP5 No reputable external source classification for this exact variant was identified that could support PP5.

Benign

BA1 Population frequency does not reach the BA1 threshold of 1%.

BS1 Population frequency does not exceed the default non-VCEP BS1 threshold of 0.3%.

BS2 The reviewed data do not establish observation of this variant in a number of healthy individuals sufficient for BS2.

BS3 No well-established functional or RNA study showing a normal effect for this exact variant was identified.

BS4 No family study showing lack of segregation with disease was identified for this variant.

BP2 No phase data were identified to determine whether this variant occurs in trans with a pathogenic variant or in cis with another variant.

BP5 No alternate molecular explanation for disease was identified in the reviewed materials, so BP5 was not assessed.

BP6 No reputable benign external classification was identified for this exact variant.

BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact, but the reviewed sources did not provide nucleotide conservation evidence needed for a complete BP7 assessment.

N/A · 8 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.07239e-05; MAF= 0.00107%, 13/1212241 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.45152e-05; MAF= 0.00145%, 13/895613 alleles, homozygotes = 0); grpmax FAF= 8.1e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.6371e-05; MAF= 0.00164%, 3/183251 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.66928e-05; MAF= 0.00367%, 3/81760 alleles, homozygotes = 0); grpmax FAF= 9.75e-06.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0011% · 13 / 1,212,241
0 hom · FAF 0.00081%

European (non-Finnish)

13 / 895,613

0.0015%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0016% · 3 / 183,251
0 hom · FAF 0.00097%

European (non-Finnish)

3 / 81,760

0.0037%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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