Variant classification summary

NM_016215.4:c.812_815del

EGFL7 · NP_057299.1:p.(Lys271ThrfsTer37) · NM_016215.4

GRCh37: chr9:139566723 CAAGA>C · GRCh38: chr9:136672271 CAAGA>C

Gene: EGFL7 Transcript: NM_016215.4

Final call

VUS

PVS1 moderate PM2 supporting

Variant details

Gene

EGFL7

Transcript

NM_016215.4

Protein

NP_057299.1:p.(Lys271ThrfsTer37)

gnomAD AF

0.00020454917362133857 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_016215.4:c.812_815del is a frameshift deletion in exon 11 of EGFL7, predicted to cause a C-terminal truncation (p.Lys271ThrfsTer37). Under the ClinGen SVI PVS1 framework (PMC6185798), frameshift variants in the terminal exon with potential NMD escape are downgraded to moderate strength. The supporting literature for EGFL7 germline loss-of-function mechanism requires additional validation — the PMIDs cited in gene context review (35282432, 42009739) do not directly mention EGFL7 in their full text. The variant is extremely rare in population databases (gnomAD v4.1 AF=0.02045%) meeting PM2 at supporting level.

2

This variant is absent from ClinVar with no clinical assertions, no functional studies, and no segregation data. No publications were identified that specifically mention NM_016215.4:c.812_815del.

3

With one moderate criterion (PVS1) and one supporting criterion (PM2) under the generic ACMG/AMP 2015 classification framework (PMID:25741868), this variant does not meet the threshold for Likely Pathogenic (requires 1 Strong + 1-2 Moderate, or 1 Very Strong + 1 Moderate, or 3 Moderate, or 2 Moderate + 2 Supporting, or 1 Moderate + 4 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	Met	NM_016215.4:c.812_815del is a frameshift variant predicted to result in premature termination (NP_057299.1:p.Lys271ThrfsTer37) occurring in the terminal exon (exon 11/11). The EGFL7 protein is 274 amino acids; truncation at residue 271 removes only the last 3 residues and appends 37 novel amino acids before a premature stop. Under ClinGen SVI PVS1 recommendations (PMC6185798), C-terminal truncations in the last exon with potential NMD escape are downgraded from very strong to moderate. The gene-level evidence for EGFL7 germline loss-of-function disease mechanism requires further validation — literature review identified candidate disease associations but the specific PMIDs cited (35282432, 42009739) do not directly mention EGFL7 in their full text.	pvs1_generic_framework
PS1	N/A	PS1 applies when the same amino acid change as an established pathogenic variant is produced by a different nucleotide change; this is a frameshift deletion, not a nucleotide substitution amenable to PS1.
PS2	Not met	No de novo observation has been reported for NM_016215.4:c.812_815del in any publication or clinical database reviewed.
PS3	Not met	No functional data exists for NM_016215.4:c.812_815del or a systematically characterized range that includes residue 271 of EGFL7. No publications were identified that tested this variant experimentally. Domain-level inference alone is insufficient for PS3.
PS4	Not met	No case-control or cohort data are available demonstrating enrichment of NM_016215.4:c.812_815del in affected individuals. The variant is absent from ClinVar with no clinical assertions.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 derives from a well-established pathogenic variant for which reclassification as benign is considered; no such variant has been identified for EGFL7 at this locus.
PM1	Not met	The variant does not lie within a statistically significant mutational hotspot (cancerhotspots.org negative for residue K271). No functional domain data are available to establish that the variant truncates a well-characterized critical domain. Without domain-level functional annotation, PM1 cannot be applied.	oncokb
PM2	Met	NM_016215.4:c.812_815del is observed at very low frequency in population databases. In gnomAD v2.1, the overall allele frequency is 0.01320% (37/280,402 alleles, 0 homozygotes) with a grpmax FAF of 0.02238%. In gnomAD v4.1, the overall allele frequency is 0.02045% (330/1,613,304 alleles, 1 homozygote) with a grpmax FAF of 0.02392%. Both frequencies are well below the 0.1% PM2 threshold. The variant is largely restricted to the European (non-Finnish) population and is absent from most other populations.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 requires observation in trans with a pathogenic variant for recessive disorders; EGFL7 is not established as a recessive disease gene and no trans observations exist.
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. NM_016215.4:c.812_815del is a frameshift deletion resulting in a premature termination codon, not an in-frame change.
PM5	N/A	PM5 requires a different missense change at the same residue that has been established as pathogenic. This variant is a frameshift deletion, not a missense variant. No same-residue missense comparator candidates were identified.
PM6	Not met	No de novo observation has been reported for NM_016215.4:c.812_815del. PM6 requires confirmed maternity and paternity with a de novo occurrence.
PP1	Not met	No segregation data are available for NM_016215.4:c.812_815del in affected families.
PP2	N/A	PP2 applies to missense variants in genes where missense variation is an established disease mechanism and benign missense variation is low. This variant is a frameshift deletion, not a missense variant.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score = 0.00; Pangolin splice gain = 0.01, splice loss = -0.08). REVEL and BayesDel scores are not available for this deletion variant. No HCI prior probability exists for EGFL7. There is no computational evidence supporting a deleterious effect.	spliceai
PP4	Not met	No patient phenotype or clinical data are available to evaluate whether the variant carrier phenotype is consistent with an EGFL7-related disorder.
PP5	N/A	PP5 is not applicable because NM_016215.4:c.812_815del is absent from ClinVar and no reputable source has classified this variant. There is no expert panel or clinical laboratory classification to draw from.	clinvar
BA1	Not met	The variant allele frequency is 0.01320% in gnomAD v2.1 and 0.02045% in gnomAD v4.1, well below the BA1 threshold of >1% (0.01). The highest subpopulation frequency is 0.02913% in European (non-Finnish) v2.1.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency is 0.01320% in gnomAD v2.1 and 0.02045% in gnomAD v4.1, below the BS1 threshold of >0.3%. The variant is not observed at a frequency exceeding the expected prevalence of a highly penetrant disorder.	gnomad_v2 gnomad_v4
BS2	Not met	While gnomAD v4.1 reports one homozygous individual for this variant, BS2 requires observation of the variant in a healthy adult homozygous state for a fully penetrant dominant disorder. A single homozygous observation in a population database without phenotype confirmation is insufficient to apply BS2, particularly when the associated disease penetrance is not well established.	gnomad_v4
BS3	Not met	No functional data exist demonstrating that NM_016215.4:c.812_815del has no deleterious effect on protein function. No experimental studies testing this variant were identified.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease in affected families.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the predominant cause of disease. This variant is a frameshift truncating variant, not a missense variant.
BP2	Not met	No observation of NM_016215.4:c.812_815del in trans with a known pathogenic variant in EGFL7 has been reported.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This variant is a frameshift deletion, not an in-frame change in a repetitive region.
BP4	Not met	SpliceAI predicts no significant splice impact (max delta score = 0.00) and Pangolin splice scores are weak (SG=0.01, SL=-0.08). However, multiple lines of computational evidence are needed to support BP4, and REVEL/BayesDel scores are not available for this deletion variant. A single computational source predicting no impact is insufficient to apply BP4.	spliceai
BP5	N/A	BP5 requires an alternative molecular basis for disease that fully explains the phenotype. Without clinical phenotype data or an identified alternative causative variant, BP5 cannot be applied.
BP6	N/A	BP6 is not applicable because NM_016215.4:c.812_815del is absent from ClinVar and no reputable source has classified this variant as benign. There is no clinical laboratory or expert panel assertion to draw from.	clinvar
BP7	N/A	BP7 applies to synonymous variants where splicing prediction algorithms predict no impact on the splice consensus sequence. NM_016215.4:c.812_815del is a frameshift deletion, not a synonymous variant.

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