NM_023067.4:c.297_311del

FOXL2 · NP_075555.1:p.(Gln99_Arg103del) · NM_023067.4

GRCh37: chr3:138665253 GTGGCGGATGCTATTT>G · GRCh38: chr3:138946411 GTGGCGGATGCTATTT>G

Gene: FOXL2 Transcript: NM_023067.4

Final call

VUS

PM2 supporting PM4 moderate

Variant details

Gene

FOXL2

Transcript

NM_023067.4

Protein

NP_075555.1:p.(Gln99_Arg103del)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_023067.4:c.297_311del (p.Gln99_Arg103del) is an in-frame deletion of 15 nucleotides in exon 1 of FOXL2, removing five amino acids (Q99-R103) in a non-repeat region of the gene. Under generic ACMG/AMP 2015, this qualifies for PM4 at moderate strength.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the <0.1% allele frequency threshold for PM2 at supporting level.

PVS1 is not met: the variant is an in-frame deletion that does not fall into the default null-variant buckets under PMC6185798 (nonsense, frameshift, or canonical splice). The pvs1_variant_assessment confirms generic PVS1 is not applicable.

No functional studies, de novo data, cosegregation data, case-control data, computational evidence of deleteriousness, or ClinVar classification are available for this variant.

Total evidence: 1 moderate (PM4) + 1 supporting (PM2). Under ACMG/AMP 2015 combination rules (PMID:25741868), this is insufficient for likely pathogenic (which requires ≥2 moderate or ≥1 moderate + ≥2 supporting). The variant is classified as a Variant of Uncertain Significance (VUS).

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	Not met	NM_023067.4:c.297_311del is an in-frame deletion of 15 nucleotides in exon 1, predicted to remove 5 amino acids (p.Gln99_Arg103del) without disrupting the reading frame. This variant does not fall into the default PVS1 null-variant buckets defined by PMC6185798 (nonsense, frameshift, or canonical ±1,2 splice consensus variants). The pvs1_variant_assessment confirms apply_generic_pvs1_framework is false and variant_bucket is 'other'. While FOXL2 loss-of-function is a known mechanism for blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), this specific in-frame deletion does not meet PVS1 criteria.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	PS1 applies when a different nucleotide change is predicted to produce the same amino acid change as an established pathogenic variant. This is an in-frame deletion, not a nucleotide substitution, and there is no alternative nucleotide change that could produce the identical p.(Q99_R103del) protein consequence.
PS2	Not met	No de novo data are available for NM_023067.4:c.297_311del. PS2 requires confirmation that the variant occurred de novo with confirmed maternity and paternity in a patient with a phenotype consistent with the gene.
PS3	Not met	No functional studies have been identified for NM_023067.4:c.297_311del (p.Gln99_Arg103del). OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No literature reports experimental characterization of this specific variant or a systematically characterized range that includes residues Q99-R103. Domain-level inference from sparse testing of nearby residues does not satisfy PS3 requirements.	oncokb
PS4	Not met	No case-control or prevalence data are available for this variant. It is absent from ClinVar and all queried population databases, providing no evidence of enrichment in affected individuals relative to controls.
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 classification framework (PMID:25741868). The standard pathogenic criteria are PVS1, PS1-PS4, PM1-PM6, PP1-PP5.
PM1	Not met	The deleted region (residues Q99-R103) lies in the N-terminal region of FOXL2 outside well-characterized functional domains such as the forkhead DNA-binding domain (residues ~151-250). Cancerhotspots.org does not identify a statistically significant hotspot at this position. While the N-terminal region contributes to transcriptional regulation, the specific 5-residue segment Q99-R103 has not been characterized as a critical, well-established functional domain without benign variation sufficient to satisfy PM1.
PM2	Met	NM_023067.4:c.297_311del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP 2015, absence from population databases supports pathogenicity at a supporting level (allele frequency < 0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM4	Met	NM_023067.4:c.297_311del is an in-frame deletion removing 15 nucleotides and 5 amino acids (p.Gln99_Arg103del) in exon 1 of FOXL2. The deletion occurs in a non-repeat region of the gene — it lies upstream of the polyalanine tract at residues 221-234 and is distinct from the poly-glycine (residues ~57-68) and poly-proline (residues 88-99) tracts. In-frame deletions in non-repeat regions that alter protein length are considered moderate evidence of pathogenicity under generic ACMG/AMP 2015.
PM5	N/A	PM5 applies to novel missense variants occurring at the same amino acid residue as a previously established pathogenic missense change. This variant is an in-frame deletion, not a missense substitution. The pm5_candidates assessment confirms ineligibility for classic same-residue PM5 semantics.	pm5_candidates
PM6	Not met	No de novo confirmation data are available for this variant. PM6 requires a de novo observation without confirmation of paternity and maternity. No published or database reports of de novo occurrence were identified.
PP1	Not met	No cosegregation data are available for NM_023067.4:c.297_311del. PP1 requires demonstration that the variant cosegregates with disease in multiple affected family members.
PP2	N/A	PP2 applies to missense variants in genes where missense variants are a known mechanism and benign missense variation is rare. This variant is an in-frame deletion, not a missense substitution.
PP3	Not met	No computational evidence supports a deleterious effect for this variant. SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not applicable to insertion-deletion variants. HCI prior scores are not available for FOXL2. Without multiple concordant in silico predictions of deleteriousness, PP3 cannot be applied.	spliceai
PP4	Not met	No patient phenotype data are available for comparison to the FOXL2-associated disease spectrum (blepharophimosis, ptosis, epicanthus inversus syndrome / BPES; premature ovarian insufficiency). PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	NM_023067.4:c.297_311del is absent from ClinVar with no classification from any submitter, including expert panels. PP5 requires that a reputable source has previously reported the variant as pathogenic.	clinvar
BA1	Not met	NM_023067.4:c.297_311del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency > 1% in any population database, which is not met.	gnomad_v2 gnomad_v4
BS1	Not met	NM_023067.4:c.297_311del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BS1 requires an allele frequency > 0.3% in population databases under generic ACMG, which is not met.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding the observation of this variant in healthy adults. BS2 requires observation in a healthy adult individual for a recessive, X-linked, or fully penetrant dominant disorder expected to manifest at an early age.
BS3	Not met	No well-established functional studies demonstrate a neutral or non-deleterious effect for NM_023067.4:c.297_311del. No experimental data characterizing the functional impact of deleting residues Q99-R103 in FOXL2 were identified.
BS4	Not met	No segregation data are available. BS4 requires lack of cosegregation of the variant with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary known disease mechanism. This variant is an in-frame deletion, not a missense substitution.
BP2	Not met	No data are available on whether NM_023067.4:c.297_311del has been observed in trans with a known pathogenic FOXL2 variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	Not met	The deleted region (residues Q99-R103) is not in a repetitive region of FOXL2. The known repetitive elements in FOXL2 include a polyalanine tract at residues 221-234, a poly-glycine tract at approximately residues 57-68, and a poly-proline tract at residues 88-99. Residues Q99-R103 are immediately C-terminal to the poly-proline tract but do not themselves constitute a repetitive region. BP3 is therefore not applicable.
BP4	Not met	Multiple lines of computational evidence do not conclusively suggest a benign impact. SpliceAI predicts no splice alteration (max delta 0.00), but this only addresses splicing and does not evaluate the protein-level consequence of a 5-amino-acid in-frame deletion. REVEL and BayesDel are not applicable to indels. Without multiple concordant computational predictions unequivocally supporting a benign interpretation, BP4 cannot be applied.	spliceai
BP5	Not met	No data are available regarding observation of this variant in a case with an alternative molecular basis for disease. BP5 requires that the variant be found in an individual with an alternate confirmed molecular cause.
BP6	Not met	NM_023067.4:c.297_311del is absent from ClinVar. No reputable source has reported this variant as benign. BP6 requires a reputable source to have classified the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or creation of a new splice site. This variant is an in-frame deletion, not a synonymous substitution.

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