About ASXL1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ASXL1 c.2281G>A, p.(Ala761Thr)
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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple computational results support no damaging effect. REVEL is low at 0.09, BayesDel is negative at -0.340274, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00.
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: BP4 supporting; combination = 1 supporting benign, 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
90 / 1,614,034 alleles
gnomAD v4.1: 90 / 1,614,034 alleles. Recorded AF 5.57609e-05. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000123308; MAF= 0.01233%, 31/251404 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00097988; MAF= 0.09799%, 30/30616 alleles, homozygotes = 0); grpmax FAF= 0.00070517.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Likely benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ASXL1, a tumor suppressor and epigenetic regulator, is inactivated by mutation in various cancer types, most frequently in myeloid malignancies.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV60105533, n = 2 times).
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: 1 met · 8 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.2281G>A (p.Ala761Thr) variant has been reported in ClinVar as Likely benign by a single submitter.
This variant is present in gnomAD, with a highest observed South Asian allele frequency of 0.09799% (30/30,616) in v2.1 and 0.09442% (86/91,078) in v4.1, which is below the default BS1 threshold of 0.3% and BA1 threshold of 1.0%.
Computational evidence does not support a damaging effect: REVEL is 0.09, BayesDel is -0.340274, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
No criteria match.
Met · 1
BP4 SupportingMultiple computational results support no damaging effect. REVEL is low at 0.09, BayesDel is negative at -0.340274, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
- REVEL 0.09
- BayesDel -0.340274
- SpliceAI max delta 0.00
Sources
Not met · 8 · evaluated, threshold not reached
PS1 No evidence was identified that a different nucleotide change produces the same amino acid substitution with an established pathogenic or likely pathogenic classification. Details ▾Hide ▴
Evidence considered
- ClinVar exact-variant review did not identify a qualifying PS1 comparator
Still missing
- No qualifying same-amino-acid pathogenic comparator was identified.
Sources
PS4 Available evidence does not show that this variant is enriched in affected individuals compared with controls, and it is present in population databases. Details ▾Hide ▴
Evidence considered
- ClinVar has a single likely benign submission
- Variant is present in gnomAD v2.1 and v4.1
Still missing
- No affected-versus-control enrichment data were identified
- No exact-variant case series supporting increased prevalence in affected individuals were identified
Sources
PM1 Available evidence does not support that p.Ala761Thr lies in a well-established mutational hotspot or a critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review found no significant hotspot row for A761
Still missing
- No domain-specific evidence supporting a critical benign-variant-depleted region was identified
- Cancer Hotspots review did not show a statistically significant hotspot at this residue
Sources
PM2 This variant is present in population databases, including a highest observed South Asian allele frequency of 0.09799% in gnomAD v2.1 and 0.09442% in gnomAD v4.1. Although these values are below the default 0.1% PM2 cutoff, the variant is observed recurrently in population datasets and was not treated as convincingly rare for ACMG PM2 evidence. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 South Asian AF 0.09799% (30/30616)
- gnomAD v4.1 South Asian AF 0.09442% (86/91078)
- including 1 homozygote
Sources
PP2 Available evidence does not show that missense variation is a common established disease mechanism for ASXL1, so PP2 was not applied. Details ▾Hide ▴
Evidence considered
- ASXL1 germline disease context supports loss of function rather than a clearly established missense-driven mechanism
Sources
pvs1_gene_context
PP3 Computational evidence does not support a damaging effect. REVEL is 0.09, BayesDel is -0.340274, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
- REVEL 0.09
- BayesDel -0.340274
- SpliceAI max delta 0.00
Sources
BA1 Population frequency does not reach the default BA1 threshold of 1.0%. The highest observed population frequency is 0.09799% in gnomAD v2.1 and 0.09442% in gnomAD v4.1, both below 1.0%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 South Asian AF 0.09799%
- gnomAD v4.1 South Asian AF 0.09442%
Sources
BS1 Population frequency does not exceed the default BS1 threshold of 0.3%. The highest observed population frequency is 0.09799% in gnomAD v2.1 and 0.09442% in gnomAD v4.1, both below 0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 South Asian AF 0.09799%
- gnomAD v4.1 South Asian AF 0.09442%
Sources
Not assessed · 12 · no assessment recorded
PS2 No confirmed de novo occurrence with parental testing and phenotype details was identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar record review did not provide de novo evidence
Still missing
- No parental testing data were identified
- No phenotype-matched de novo case report was identified
Sources
PS3 No well-established functional study showing a damaging effect for this specific variant was identified. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No variant-specific functional assay was identified
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Still missing
- No phase data were identified
- No recessive case data were identified
PM6 No assumed de novo report without confirmed parentage was identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar review did not provide PM6-type evidence
Still missing
- No parentally unconfirmed de novo case was identified
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- No family segregation report was identified
PP4 No phenotype-specific evidence was identified showing that the reported clinical presentation is highly specific for a disease caused by ASXL1. Details ▾Hide ▴
Still missing
- No patient phenotype data were provided for PP4 assessment
BS2 The variant is observed in gnomAD, including one homozygote in v4.1, but the available data do not confirm healthy status, age, or phenotype sufficiently to apply BS2 confidently. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 includes 1 homozygote
Still missing
- No confirmed healthy adult carrier data were identified
Sources
BS3 No well-established functional study showing normal or near-normal function for this variant was identified. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No benign functional assay was identified
Sources
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- No family study showing lack of segregation with disease was identified
BP1 ASXL1-related germline disease is strongly associated with loss-of-function variants, but the available evidence in this case was not considered sufficient on its own to apply BP1. Details ▾Hide ▴
Evidence considered
- ASXL1 loss of function is an established germline mechanism
Still missing
- No explicit gene-specific BP1 rule was available
Sources
pvs1_gene_context
BP2 No data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant. Details ▾Hide ▴
Still missing
- No phase information was identified
BP5 No evidence was identified for an alternate molecular explanation for disease in the same individual. Details ▾Hide ▴
Still missing
- No broader genotype context was available
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, not a nonsense, frameshift, or canonical +/-1 or 2 splice-site variant, so the generic PVS1 loss-of-function framework does not apply. Details ▾Hide ▴
Evidence considered
- ASXL1 loss of function is an established germline disease mechanism
- c.2281G>A produces p.(Ala761Thr) and is outside the generic null-variant PVS1 buckets
Sources
PM4 N/AThis variant is a missense substitution and does not cause a protein length change or in-frame insertion or deletion. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala761Thr)
PM5 N/AClassic same-residue PM5 semantics could not be confirmed safely for this case, and no qualifying pathogenic comparator variants were identified. Details ▾Hide ▴
Evidence considered
- PM5 candidate review found no eligible same-residue comparators and marked classic PM5 as not confirmed
Sources
pm5_candidates
PP5 N/APP5 was not applied because no qualifying reputable-source pathogenic assertion independent of the underlying evidence review was identified. Details ▾Hide ▴
Evidence considered
- ClinVar shows a likely benign single-submitter assertion
- not a qualifying pathogenic reputable-source assertion
Sources
BP3 N/AThis variant is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
Evidence considered
- Protein consequence is a missense substitution
BP6 N/ABP6 was not applied because the available ClinVar entry is a single-submitter likely benign assertion and does not meet a separate reputable-source criterion for benign classification without independent evidence review. Details ▾Hide ▴
BP7 N/AThis variant is missense rather than synonymous, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala761Thr)
Identifiers
- Gene
- ASXL1
- Transcript
- NM_015338.5
- Coding (HGVS c.)
- NM_015338.5:c.2281G>A
- Protein (HGVS p.)
- NP_056153.2:p.(Ala761Thr)
- GRCh38
- chr20:32434993 G>A
- GRCh37
- chr20:31022796 G>A
- ClinVar
- 1948898
- COSMIC
- COSV60105533
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
90 / 1,614,034 alleles
AF 5.58e-05 · 1 homozygotes · FAF 0.000782
gnomAD v2.1
31 / 251,404 alleles
AF 0.000123 · 0 homozygotes · FAF 0.000705
By genetic ancestry
gnomAD v4.1
AF 5.6e-05 · 90 / 1,614,034 alleles · 1 hom · FAF 0.00078
| South Asian86 / 91,078 | 0.000941 hom |
| Remaining individuals2 / 62,486 | 3.2e-05 |
| African/African American2 / 74,916 | 2.7e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 0.00012 · 31 / 251,404 alleles · 0 hom · FAF 0.00071
| South Asian30 / 30,616 | 0.00098 |
| African/African American1 / 16,240 | 6.2e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.57609e-05; MAF= 0.00558%, 90/1614034 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000944246; MAF= 0.09442%, 86/91078 alleles, homozygotes = 1); grpmax FAF= 0.00078238.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000123308; MAF= 0.01233%, 31/251404 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00097988; MAF= 0.09799%, 30/30616 alleles, homozygotes = 0); grpmax FAF= 0.00070517.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.090
- BayesDel
- -0.340
How the predictions were used
BP4 SupportingMultiple computational results support no damaging effect. REVEL is low at 0.09, BayesDel is negative at -0.340274, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
- REVEL 0.09
- BayesDel -0.340274
- SpliceAI max delta 0.00
Sources
PP3 Computational evidence does not support a damaging effect. REVEL is 0.09, BayesDel is -0.340274, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
- REVEL 0.09
- BayesDel -0.340274
- SpliceAI max delta 0.00
Sources
BP7 N/AThis variant is missense rather than synonymous, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala761Thr)
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.09. BayesDel score = -0.340274.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
90 / 1,614,034 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
1 Likely benign
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/variation/1948898/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/20-31022796-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr20-32434993-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_015338.5%3Ac.2281…
- OncoKB ↗www.oncokb.org/gene/ASXL1/A761T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123587090
- 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= 5.57609e-05; MAF= 0.00558%, 90/1614034 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000944246; MAF= 0.09442%, 86/91078 alleles, homozygotes = 1); grpmax FAF= 0.00078238.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000123308; MAF= 0.01233%, 31/251404 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00097988; MAF= 0.09799%, 30/30616 alleles, homozygotes = 0); grpmax FAF= 0.00070517.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1948898)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.09. BayesDel score = -0.340274.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ASXL1, a tumor suppressor and epigenetic regulator, is inactivated by mutation in various cancer types, most frequently in myeloid malignancies.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV60105533, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.