NM_021946.4:c.3143G>A

BCORL1 · NP_068765.3:p.(Arg1048Gln) · NM_021946.4

GRCh37: chrX:129149891 G>A · GRCh38: chrX:130015915 G>A

Gene: BCORL1 Transcript: NM_021946.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

BCORL1

Transcript

NM_021946.4

Protein

NP_068765.3:p.(Arg1048Gln)

gnomAD AF

0.0003834482576243397 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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	This 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.	pvs1_generic_framework
PS1	N/A	No 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.	clinvar
PS2	Not met	No de novo observation has been reported for NM_021946.4:c.3143G>A in the available literature or databases.
PS3	Not met	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.	oncokb
PS4	Not met	No case-control studies or statistically significant enrichment of this variant in affected individuals versus controls has been reported.
PS5	Not met	This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source or clinical laboratory.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	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.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant. PM6 requires a confirmed de novo occurrence with or without confirmed parentage.
PP1	Not met	No cosegregation data are available for this variant in affected families.
PP2	Not assessed	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.
PP3	Not met	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.	bayesdel spliceai
PP4	Not met	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.
PP5	Not met	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.	clinvar
BA1	Not met	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%.	gnomad_v2 gnomad_v4
BS1	Not met	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%.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v4
BS3	Not met	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.	oncokb
BS4	Not met	No non-segregation data are available for this variant in affected families.
BP1	Not met	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.
BP2	Not met	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.
BP4	Met	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.	bayesdel spliceai
BP5	Not met	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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 is only applicable to synonymous (silent) variants with no predicted splicing impact. This variant is a missense substitution (c.3143G>A, p.Arg1048Gln).
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions without known function. This is a substitution variant.
PM3	N/A	PM3 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.
PM4	N/A	PM4 applies to protein-length-altering variants (in-frame deletions/insertions, stop-loss). This is a single-nucleotide missense substitution.

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