About EGFL7
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
EGFL7 c.812_815del, p.(Lys271ThrfsTer37)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Moderate
PVS1 · moderate
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.
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 moderate, PM2 supporting; combination = 1 moderate + 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
330 / 1,613,304 alleles
gnomAD v4.1: 330 / 1,613,304 alleles. Recorded AF 0.000204549. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000131953; MAF= 0.01320%, 37/280402 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00029132; MAF= 0.02913%, 37/127008 alleles, homozygotes = 0); grpmax FAF= 0.00022376.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 15 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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).
No criteria match.
Met · 2
PVS1 ModerateNM_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. Details ▾Hide ▴
Evidence considered
- Frameshift variant c.812_815del predicted to cause p.Lys271ThrfsTer37
- Variant in terminal exon (11/11) with potential NMD escape — downgraded per PMC6185798
- EGFL7 germline LoF mechanism flagged by gene context review but supporting literature citations require verification
Still missing
- Confirm EGFL7 germline disease association and LoF mechanism with validated literature
- Verify that the C-terminal truncation removes a functionally critical domain
- The two PMIDs cited in pvs1_gene_context (35282432
- 42009739) do not mention EGFL7 in full text
Sources
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.01320% (37/280
- 402)
- grpmax FAF=0.02238%
- gnomAD v4.1: AF=0.02045% (330/1
- 613
- 304)
- grpmax FAF=0.02392%
- gnomAD Canada: absent
- Both overall and grpmax FAF below 0.1% threshold
Sources
Not met · 15 · evaluated, threshold not reached
PS2 No de novo observation has been reported for NM_016215.4:c.812_815del in any publication or clinical database reviewed. Details ▾Hide ▴
Evidence considered
- No de novo report found in literature or ClinVar
Still missing
- No parental testing data available
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect — no variant-specific functional data curated
- No publications identified with functional characterization of this variant
Still missing
- No experimental functional studies available for this variant or its protein domain
PS4 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. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar — no clinical cases recorded
- Present in gnomAD population databases at low frequency
- suggesting background population carriage
Still missing
- No case-control studies available
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: no significant hotspot at residue K271
- OncoKB: EGFL7 is a secreted pro-angiogenic factor
- infrequently mutated
- no domain-level functional data for PM1
Still missing
- No functional domain characterization available for the C-terminal region of EGFL7
Sources
PM6 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. Details ▾Hide ▴
Evidence considered
- No de novo report identified in any source reviewed
Still missing
- No parental testing data available
PP1 No segregation data are available for NM_016215.4:c.812_815del in affected families. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data found
Still missing
- No segregation analysis available
PP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 — no predicted splice alteration
- Pangolin: SG=0.01
- SL=-0.08 — weak prediction scores
- REVEL/BayesDel: not applicable (deletion
- not SNV)
- HCI prior: gene not supported
Sources
PP4 No patient phenotype or clinical data are available to evaluate whether the variant carrier phenotype is consistent with an EGFL7-related disorder. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data provided for variant carriers
Still missing
- Patient phenotype information not available
BA1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF=0.01320% — below BA1 >1% threshold
- gnomAD v4.1 total AF=0.02045% — below BA1 >1% threshold
- Maximum subpopulation AF in v4.1 NFE: 0.02636%
Sources
BS1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF=0.01320% — below BS1 >0.3% threshold
- gnomAD v4.1 total AF=0.02045% — below BS1 >0.3% threshold
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1 homozygous individual reported
- No phenotype data available to confirm healthy adult status of the homozygote
Still missing
- Phenotype of the homozygous individual is unknown
- EGFL7 disease penetrance not established
Sources
BS3 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. Details ▾Hide ▴
Evidence considered
- No functional studies demonstrating benign effect identified
Still missing
- No experimental functional data available
BS4 No segregation data are available to demonstrate lack of cosegregation with disease in affected families. Details ▾Hide ▴
Evidence considered
- No family segregation studies available
Still missing
- No segregation data
BP2 No observation of NM_016215.4:c.812_815del in trans with a known pathogenic variant in EGFL7 has been reported. Details ▾Hide ▴
Evidence considered
- No in trans observations reported
Still missing
- No phase data available
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice alteration
- Pangolin scores weak (SG=0.01
- SL=-0.08)
- REVEL/BayesDel not applicable for deletion
Still missing
- Limited computational evidence available for deletion variants
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 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. Details ▾Hide ▴
No further detail was recorded.
PM3 N/APM3 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. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 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. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 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. Details ▾Hide ▴
Evidence considered
- Frameshift variant — no same-residue missense comparator available
- PM5 candidate harvesting confirmed not applicable
PP2 N/APP2 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. Details ▾Hide ▴
No further detail was recorded.
PP5 N/APP5 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. Details ▾Hide ▴
Evidence considered
- ClinVar: absent — no classification available
- No expert panel or clinical laboratory assertion exists
Sources
BP1 N/ABP1 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. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 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. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ABP5 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. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 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. Details ▾Hide ▴
Evidence considered
- ClinVar: absent — no benign classification available
- No expert panel or clinical laboratory benign assertion exists
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 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. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- EGFL7
- Transcript
- NM_016215.4
- Coding (HGVS c.)
- NM_016215.4:c.812_815del
- Protein (HGVS p.)
- NP_057299.1:p.(Lys271ThrfsTer37)
- GRCh38
- chr9:136672271 CAAGA>C
- GRCh37
- chr9:139566723 CAAGA>C
Gene diagram
Every interpreted variant in EGFL7, mapped onto the exon structure of NM_016215.4. Select a row to find it on the plot.
EGFL7NM_016215.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in EGFL7
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
330 / 1,613,304 alleles
AF 0.000205 · 1 homozygotes · FAF 0.000239
gnomAD v2.1
37 / 280,402 alleles
AF 0.000132 · 0 homozygotes · FAF 0.000224
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.0002 · 330 / 1,613,304 alleles · 1 hom · FAF 0.00024
| European (non-Finnish)311 / 1,179,958 | 0.000261 hom |
| Remaining individuals11 / 62,466 | 0.00018 |
| European (Finnish)4 / 63,380 | 6.3e-05 |
| African/African American3 / 74,934 | 4e-05 |
| South Asian1 / 91,092 | 1.1e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00013 · 37 / 280,402 alleles · 0 hom · FAF 0.00022
| European (non-Finnish)37 / 127,008 | 0.00029 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000204549; MAF= 0.02045%, 330/1613304 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000263569; MAF= 0.02636%, 311/1179958 alleles, homozygotes = 1); grpmax FAF= 0.00023919.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000131953; MAF= 0.01320%, 37/280402 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00029132; MAF= 0.02913%, 37/127008 alleles, homozygotes = 0); grpmax FAF= 0.00022376.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 — no predicted splice alteration
- Pangolin: SG=0.01
- SL=-0.08 — weak prediction scores
- REVEL/BayesDel: not applicable (deletion
- not SNV)
- HCI prior: gene not supported
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice alteration
- Pangolin scores weak (SG=0.01
- SL=-0.08)
- REVEL/BayesDel not applicable for deletion
Still missing
- Limited computational evidence available for deletion variants
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
330 / 1,613,304 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_016215.4%3Ac.812_815del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-139566723-CAAGA-C?dataset=g…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-136672271-CAAGA-C?datase…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-136672271-CAAGA-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_016215.4%3Ac.812_…
- OncoKB ↗www.oncokb.org/gene/EGFL7/K271Tfs*37
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=EGFL7+c.812_815del
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000204549; MAF= 0.02045%, 330/1613304 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000263569; MAF= 0.02636%, 311/1179958 alleles, homozygotes = 1); grpmax FAF= 0.00023919.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000131953; MAF= 0.01320%, 37/280402 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00029132; MAF= 0.02913%, 37/127008 alleles, homozygotes = 0); grpmax FAF= 0.00022376.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.