NM_021946.4:c.1111A>C

BCORL1 · NP_068765.3:p.(Thr371Pro) · NM_021946.4

GRCh37: chrX:129147859 A>C · GRCh38: chrX:130013883 A>C

Gene: BCORL1 Transcript: NM_021946.4

Final call

VUS

BP4 supporting

Variant details

Gene

BCORL1

Transcript

NM_021946.4

Protein

NP_068765.3:p.(Thr371Pro)

gnomAD AF

0.00024711632757896045 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	BCORL1 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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	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.	clinvar pm5_candidates
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant.	clinvar
PS3	Not assessed	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.	oncokb
PS4	Not assessed	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.	clinvar
PM1	Not met	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.	hotspots oncokb
PM2	Not met	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.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is a recessive-phase criterion, and no recessive biallelic context was identified for this X-linked BCORL1 missense variant.
PM4	N/A	This variant is a missense substitution and does not change protein length, so PM4 does not apply.
PM5	Not assessed	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.	pm5_candidates clinvar
PM6	Not assessed	No presumed de novo observation without full parentage confirmation was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	Not assessed	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.	pvs1_gene_context
PP3	Not met	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.	spliceai bayesdel
PP4	Not assessed	No individual-level phenotype information was available to determine whether the clinical presentation is highly specific for a BCORL1-related disorder.
PP5	Not assessed	No reputable clinical source classification for this variant was identified because the variant is absent from ClinVar.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals in a context sufficient to support BS2.
BS3	Not assessed	No well-established functional study demonstrating a normal effect for this variant was identified.	oncokb
BS4	Not assessed	No non-segregation evidence was identified for this variant.
BP1	Not assessed	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.	pvs1_gene_context
BP2	Not assessed	No phase data or second-variant context was identified to support BP2.
BP3	N/A	This variant is a single amino acid substitution and not an in-frame insertion or deletion in a repetitive region, so BP3 does not apply.
BP4	Met	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.	spliceai bayesdel
BP5	Not assessed	No alternate molecular explanation for the phenotype was provided, so BP5 was not assessed.
BP6	Not assessed	No reputable external benign classification was identified because the variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 is not applicable because this variant is missense rather than synonymous or deep intronic, even though SpliceAI predicts no significant splice effect.	spliceai

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