About ASXL1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ASXL1 c.2822del, p.(Pro941LeufsTer4)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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
PVS1Strong
PVS1 · strong
This variant is a frameshift change predicted to produce p.(Pro941LeufsTer4), truncating the protein after four altered amino acids. ASXL1 loss of function is supported as a disease mechanism, so generic PVS1 assessment is appropriate; however, full very-strong weighting is not assigned from the available evidence because transcript-specific NMD and distal-region considerations were not fully resolved.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the non-VCEP PM2 threshold of 0.1%. This supports rarity in the general population.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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.
28 criteria with recorded statuses: 2 met · 7 not met · 12 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The ASXL1 c.2822del (p.(Pro941LeufsTer4)) variant has been observed in somatic cancers and is absent from ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the 0.1% PM2 threshold and supports rarity in the general population.
Published studies and OncoKB support damaging loss-of-function biology for ASXL1 truncating variants, but available data do not provide a validated germline functional assay for this specific variant.
This single-base deletion causes a frameshift predicted to truncate the protein after four altered amino acids, removing 598 of 1542 residues (38.8%), and SpliceAI predicts no significant additional splice effect with a maximum delta score of 0.02.
No criteria match.
Met · 2
PVS1 StrongThis variant is a frameshift change predicted to produce p.(Pro941LeufsTer4), truncating the protein after four altered amino acids. ASXL1 loss of function is supported as a disease mechanism, so generic PVS1 assessment is appropriate; however, full very-strong weighting is not assigned from the available evidence because transcript-specific NMD and distal-region considerations were not fully resolved. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 with ClinGen SVI PVS1 recommendations fallback
Evidence considered
- Frameshift variant NM_015338.5:c.2822del with protein consequence NP_056153.2:p.(Pro941LeufsTer4).
- Gene-level review supports ASXL1 loss of function as an established disease mechanism.
- Generic ClinGen SVI PVS1 framework applies to frameshift variants once LoF is established for the gene.
Still missing
- Transcript-specific NMD escape and functional importance of the truncated distal region could refine PVS1 strength.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the non-VCEP PM2 threshold of 0.1%. This supports rarity in the general population. Details ▾Hide ▴
Rule
ACMG/AMP PM2 at supporting strength
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
Not met · 7 · evaluated, threshold not reached
PS4 This variant has been observed in somatic cancers, but no evidence was identified showing enrichment in affected germline cases compared with controls, so PS4 is not met. Details ▾Hide ▴
PM1 This variant does not have evidence for location in a well-established mutational hotspot or a critical functional domain without benign variation, so PM1 is not met. Details ▾Hide ▴
Rule
ACMG/AMP PM1
Evidence considered
- Cancer Hotspots review did not identify a statistically significant hotspot for residue P941.
Still missing
- A validated hotspot or critical-region framework for germline ASXL1 would be needed.
Sources
PP5 This variant is absent from ClinVar, so there is no external pathogenic assertion available to support PP5. Details ▾Hide ▴
Rule
ACMG/AMP PP5
Evidence considered
- No ClinVar result found for NM_015338.5:c.2822delC.
Still missing
- A reputable pathogenic classification for this exact variant would be needed.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the benign BA1 threshold of 1%. BA1 is not met. Details ▾Hide ▴
Rule
ACMG/AMP BA1
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the benign BS1 threshold of 0.3%. BS1 is not met. Details ▾Hide ▴
Rule
ACMG/AMP BS1
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BP4 Available computational evidence does not support a benign interpretation. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, but this does not offset the predicted truncating effect of the frameshift variant. Details ▾Hide ▴
Rule
ACMG/AMP BP4
Evidence considered
- SpliceAI max delta score 0.02.
- Frameshift predicted to truncate the protein.
Sources
spliceai ↗pvs1_variant_assessment
BP6 This variant is absent from ClinVar, so there is no external benign assertion available to support BP6. Details ▾Hide ▴
Rule
ACMG/AMP BP6
Evidence considered
- No ClinVar result found for NM_015338.5:c.2822delC.
Still missing
- A reputable benign classification for this exact variant would be needed.
Sources
Not assessed · 12 · no assessment recorded
PS2 No confirmed de novo data were identified for this variant, so PS2 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP PS2
Still missing
- Confirmed maternity and paternity with a de novo occurrence would be needed.
PS3 Available studies and OncoKB support damaging biology for ASXL1 truncating variants in myeloid disease, but no well-established functional assay directly testing this specific variant in a validated germline disease framework was identified. Details ▾Hide ▴
Rule
ACMG/AMP PS3
Evidence considered
- OncoKB classifies the variant as Likely Oncogenic with likely loss-of-function biology.
- Reviewed literature concerns ASXL1 truncating biology broadly rather than this exact germline variant in a validated ACMG PS3 assay.
Still missing
- A validated functional study directly evaluating NM_015338.5:c.2822del for the relevant germline disease context would be needed.
Sources
PM3 No phase data or recessive case data were identified, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP PM3
Still missing
- Confirmed trans observations in an appropriate recessive disease context would be needed.
PM6 No assumed de novo occurrence without confirmed parentage was identified, so PM6 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP PM6
Still missing
- A de novo observation without full parental confirmation would be needed.
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP PP1
Still missing
- Family segregation data would be needed.
PP4 No phenotype information was provided that is sufficiently specific for a single genetic etiology, so PP4 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP PP4
Still missing
- Detailed clinical phenotype and diagnostic context would be needed.
BS2 No evidence was identified showing this variant in healthy adults in a manner inconsistent with disease, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP BS2
Still missing
- Observation in well-phenotyped unaffected adults would be needed.
BS3 No well-established functional study demonstrating a normal or benign effect for this specific variant was identified, so BS3 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP BS3
Evidence considered
- Available literature concerns ASXL1 truncating biology and does not show a benign effect for this specific variant.
Still missing
- A validated functional assay showing no damaging effect for this exact variant would be needed.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP BS4
Still missing
- Family data showing lack of segregation with disease would be needed.
BP2 No phase data with another variant were identified, so BP2 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP BP2
Still missing
- Phase information and a second variant in the relevant disease context would be needed.
BP3 No evidence was identified showing that this deletion lies in a repetitive region without known function, so BP3 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP BP3
Still missing
- Repeat-context or low-complexity region evidence would be needed.
BP5 No alternate molecular explanation for the phenotype was identified, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP BP5
Still missing
- A fully explanatory alternative pathogenic finding would be needed.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable because this is a frameshift deletion, not an alternate nucleotide change producing the same amino acid substitution as a known pathogenic variant. Details ▾Hide ▴
Rule
ACMG/AMP PS1
Evidence considered
- Variant type is frameshift
- not missense.
Sources
pvs1_variant_assessment
PM4 N/APM4 is not applicable because this is a frameshift loss-of-function variant that is evaluated under PVS1 rather than an in-frame length change or stop-loss event. Details ▾Hide ▴
Rule
ACMG/AMP PM4
Evidence considered
- Variant bucket is frameshift.
Sources
pvs1_variant_assessment
PM5 N/APM5 is not applicable because this variant is not a novel missense change at an amino acid residue with a previously established pathogenic missense variant. Details ▾Hide ▴
Rule
ACMG/AMP PM5
Evidence considered
- Variant type is frameshift
- not missense.
Sources
pvs1_variant_assessment
PP2 N/APP2 is not applicable because this is not a missense variant. Details ▾Hide ▴
Rule
ACMG/AMP PP2
Evidence considered
- Variant type is frameshift.
Sources
pvs1_variant_assessment
PP3 N/APP3 is not applied because this frameshift deletion is already assessed through loss-of-function evidence, and SpliceAI predicts no significant additional splice effect with a maximum delta score of 0.02. Details ▾Hide ▴
Rule
ACMG/AMP PP3
Evidence considered
- SpliceAI max delta score 0.02 indicates no significant splice impact.
- Variant type is frameshift.
Sources
spliceai ↗pvs1_variant_assessment
BP1 N/ABP1 is not applicable because this is not a missense variant. Details ▾Hide ▴
Rule
ACMG/AMP BP1
Evidence considered
- Variant type is frameshift.
Sources
pvs1_variant_assessment
BP7 N/ABP7 is not applicable because this variant is neither synonymous nor intronic. Details ▾Hide ▴
Rule
ACMG/AMP BP7
Evidence considered
- Variant type is frameshift coding deletion.
Sources
pvs1_variant_assessment
Identifiers
- Gene
- ASXL1
- Transcript
- NM_015338.5
- Coding (HGVS c.)
- NM_015338.5:c.2822del
- Protein (HGVS p.)
- NP_056153.2:p.(Pro941LeufsTer4)
- GRCh38
- chr20:32435532 GC>G
- GRCh37
- chr20:31023335 GC>G
Gene diagram
Every interpreted variant in ASXL1, mapped onto the exon structure of NM_015338.5. Select a row to find it on the plot.
ASXL1NM_015338.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ASXL1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 Available computational evidence does not support a benign interpretation. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, but this does not offset the predicted truncating effect of the frameshift variant. Details ▾Hide ▴
Rule
ACMG/AMP BP4
Evidence considered
- SpliceAI max delta score 0.02.
- Frameshift predicted to truncate the protein.
Sources
spliceai ↗pvs1_variant_assessment
PP3 N/APP3 is not applied because this frameshift deletion is already assessed through loss-of-function evidence, and SpliceAI predicts no significant additional splice effect with a maximum delta score of 0.02. Details ▾Hide ▴
Rule
ACMG/AMP PP3
Evidence considered
- SpliceAI max delta score 0.02 indicates no significant splice impact.
- Variant type is frameshift.
Sources
spliceai ↗pvs1_variant_assessment
BP7 N/ABP7 is not applicable because this variant is neither synonymous nor intronic. Details ▾Hide ▴
Rule
ACMG/AMP BP7
Evidence considered
- Variant type is frameshift coding deletion.
Sources
pvs1_variant_assessment
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
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_015338.5%3Ac.2822delC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/20-31023335-GC-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr20-32435532-GC-G?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_015338.5%3Ac.2822…
- OncoKB ↗www.oncokb.org/gene/ASXL1/P941Lfs*4
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123581795
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV60115810, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.