Classification rationale

PM2 BP7 VUS

BCORL1 c.4464C>T

The BCORL1 NM_021946.4:c.4464C>T (p.Asp1488=) variant has not been reported in ClinVar.¹ This variant is present at low frequency in gnomAD, with overall allele frequencies of 0.00396% in v2.1 and 0.00399% in v4.1; the highest observed subpopulation frequency is 0.04636% in gnomAD v4.1, which is below the 0.1% PM2 threshold and below the 0.3% BS1 threshold used here.² Computational splice prediction does not support a damaging effect, as SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the variant-level splice assessment indicates that this synonymous change is not in a canonical splice-site position.³

PM2 + BP7 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗pvs1_variant_assessment

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 · 19 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 low frequency in population databases. In gnomAD v2.1 the overall AF is 0.00396% and in gnomAD v4.1 the overall AF is 0.00399%; the highest observed subpopulation frequency in gnomAD v4.1 is 0.04636%, which is below the 0.1% threshold used here for PM2.

gnomAD v2.1 AF 3.95514e-05 (7/176985)gnomAD v4.1 AF 3.98855e-05 (48/1203445)Highest observed subpopulation AF 0.000463607 in Middle Eastern individuals

gnomad_v2 ↗gnomad_v4 ↗

BP7 supporting review Benign

This is a synonymous variant, p.(Asp1488=), and available computational evidence predicts no significant effect on splicing. SpliceAI shows a maximum delta score of 0.01, and the variant-level splice assessment indicates that it is not in a canonical splice consensus position, supporting BP7.

Synonymous protein consequence p.(Asp1488=)SpliceAI max delta score 0.01Canonical splice consensus false in variant-level assessment

spliceai ↗

Assessed · not applied · 5 not met · 14 not assessed

Pathogenic

PVS1 BCORL1 loss of function is an established germline disease mechanism, but this variant is a synonymous change, p.(Asp1488=), and the generic PVS1 assessment found that it is not a nonsense, frameshift, or canonical +/-1,2 splice-site variant.

PS2 No confirmed de novo observation with established maternity and paternity was identified for this variant.

PS3 No well-established functional study or RNA assay was identified for this exact variant, so PS3 cannot be assessed.

PS4 No enrichment data or multiple affected germline observations were identified for this exact variant, so PS4 cannot be applied.

PM1 This synonymous variant has not been shown to lie in a well-established mutational hotspot or critical functional region without benign variation.

PM6 No assumed de novo observation was identified for this variant, so PM6 cannot be assessed.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed.

PP3 Available computational evidence does not support a damaging effect.

PP4 No phenotype information specific to the tested individual was available to determine whether the clinical presentation is highly specific for a BCORL1-related disorder.

PP5 No reputable source classification for this exact germline variant was identified.

Benign

BA1 The population frequency does not meet a stand-alone benign threshold.

BS1 The population frequency is below the benign strong threshold.

BS2 Population data show rare alleles in gnomAD, but no evidence was identified demonstrating occurrence in definitively unaffected individuals at a level sufficient for BS2.

BS3 No well-established functional study showing no damaging effect was identified for this variant.

BS4 No family data were identified showing lack of segregation with disease, so BS4 cannot be assessed.

BP2 No phase information or co-occurrence data were identified for this variant, so BP2 cannot be assessed.

BP4 Computational data do not suggest splice disruption, with SpliceAI maximum delta score 0.01, but no broader multi-predictor benign framework was available for this synonymous variant beyond splice prediction alone.

BP5 No alternate molecular basis for the phenotype was provided, so BP5 cannot be assessed.

BP6 No reputable source reported this exact variant as benign or likely benign.

N/A · 7 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= 3.98855e-05; MAF= 0.00399%, 48/1203445 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000463607; MAF= 0.04636%, 2/4314 alleles, homozygotes = 0); grpmax FAF= 0.00011029.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.95514e-05; MAF= 0.00396%, 7/176985 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000169367; MAF= 0.01694%, 3/17713 alleles, homozygotes = 0); grpmax FAF= 4.577e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.004% · 48 / 1,203,445
0 hom · FAF 0.011%

Middle Eastern 2 / 4,314	0.046%
South Asian 11 / 55,844	0.02%
East Asian 2 / 33,565	0.006%
Ashkenazi Jewish 1 / 21,705	0.0046%
European (non-Finnish) 31 / 891,137	0.0035%
Remaining individuals 1 / 47,335	0.0021%

+ 4 not observed (Admixed American, European (Finnish), Amish, African/African American)

gnomAD v2.1

0.004% · 7 / 176,985
0 hom · FAF 0.0046%

South Asian 3 / 17,713	0.017%
Ashkenazi Jewish 1 / 7,020	0.014%
European (non-Finnish) 3 / 78,510	0.0038%

+ 5 not observed (African/African American, Admixed American, East Asian, European (Finnish), Remaining individuals)

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 = 0.01).

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 previously been reported in somatic cancers (COSMIC; COSV54397317, n = 5 times).

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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