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ASXL1c.3802A>GUncertain significance
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Variant interpretation report

ASXL1 c.3802A>G, p.(Thr1268Ala)

NM_015338.5:c.3802A>G NP_056153.2:p.(Thr1268Ala) View identifiers
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.

About ASXL1

No gene-level summary was recorded for this case.

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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP PM2 cutoff of 0.1% and supports rarity in population databases.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple computational results support a benign effect. REVEL is 0.098, BayesDel is -0.440581, and SpliceAI predicts no significant splice impact 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: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

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
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
COSMIC ↗Cancer Hotspots ↗
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 · 6 not met · 17 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The ASXL1 c.3802A>G (p.Thr1268Ala) variant has been reported in ClinVar as a variant of uncertain significance with one clinical laboratory submission.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.

Available computational evidence supports a benign effect, with REVEL 0.098, BayesDel -0.440581, and SpliceAI showing no predicted splice impact with a maximum delta score of 0.00.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP PM2 cutoff of 0.1% and supports rarity in population databases. Details ▾Hide ▴
Rule
Non-VCEP population rarity threshold: PM2 if allele frequency is below 0.1%; observed frequency 0 in both reviewed gnomAD datasets.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple computational results support a benign effect. REVEL is 0.098, BayesDel is -0.440581, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
  • REVEL 0.098
  • BayesDel -0.440581
  • SpliceAI max delta 0.00
Sources
revelbayesdelspliceai ↗

Not met · 6 · evaluated, threshold not reached

PVS1 ASXL1 loss of function is an established disease mechanism, but this variant is a missense substitution, not a nonsense, frameshift, or canonical +/-1 or 2 splice variant, and the generic PVS1 framework does not support applying PVS1 to this change. Details ▾Hide ▴
Rule
Generic PVS1 framework applies only to eligible null-variant classes; this variant does not meet that entry criterion.
Evidence considered
  • ASXL1 gene-level loss-of-function mechanism supported
  • Variant-level generic PVS1 scaffold indicates this missense variant is outside default null-variant buckets
Still missing
  • No RNA study specific to c.3802A>G was identified.
  • No direct evidence was identified that this missense change causes transcript loss or another null effect.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PS4 This variant has only limited observation data, with one ClinVar submission and no case-control or enrichment evidence, so increased prevalence in affected individuals has not been shown. Details ▾Hide ▴
Evidence considered
  • ClinVar uncertain significance
  • single submitter
Still missing
  • No formal enrichment study was identified.
  • No count of multiple unrelated affected individuals carrying this variant was identified.
Sources
clinvar ↗
PM1 Available evidence does not show that this variant lies in a well-established mutational hotspot or a critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots review did not identify a statistically significant hotspot
Still missing
  • No independently verified residue-level domain evidence was identified.
  • Hotspot review was marked uncertain and may need manual confirmation.
Sources
hotspots ↗
PP3 Available computational evidence does not support a damaging effect. REVEL is 0.098, BayesDel is -0.440581, and SpliceAI shows no predicted splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
  • REVEL 0.098
  • BayesDel -0.440581
  • SpliceAI max delta 0.00
Sources
revelbayesdelspliceai ↗
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the benign stand-alone threshold of greater than 1%. Details ▾Hide ▴
Rule
Non-VCEP benign stand-alone threshold: BA1 if allele frequency is greater than 1%; observed frequency 0.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the benign strong threshold of greater than 0.3%. Details ▾Hide ▴
Rule
Non-VCEP benign strong threshold: BS1 if allele frequency is greater than 0.3%; observed frequency 0.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 17 · no assessment recorded

PS1 No evidence was identified that the same amino acid change has already been established as pathogenic by a different nucleotide change. Details ▾Hide ▴
Evidence considered
  • ClinVar record reviewed
Still missing
  • No same-residue pathogenic alternate nucleotide evidence was identified.
Sources
clinvar ↗
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar review showed a single submitter and no de novo details
Still missing
  • No trio-based case report or database submission with confirmed de novo status was identified.
Sources
clinvar ↗
PS3 No well-established functional study was identified for this variant, so functional evidence supporting a damaging effect is not available. Details ▾Hide ▴
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence
Still missing
  • No validated assay result specific to p.(Thr1268Ala) was identified.
Sources
oncokb ↗
PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in an established recessive disease context. Details ▾Hide ▴
Evidence considered
  • ClinVar record reviewed
Still missing
  • No phase data were identified.
Sources
clinvar ↗
PM5 No evidence was identified that a different missense change at codon 1268 has already been established as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar record reviewed
Still missing
  • No alternate pathogenic missense variants at the same codon were identified.
Sources
clinvar ↗
PM6 No presumed de novo occurrence without confirmed parentage was identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar record reviewed
Still missing
  • No case-level inheritance data were identified.
Sources
clinvar ↗
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar record reviewed
Still missing
  • No pedigree or familial co-segregation evidence was identified.
Sources
clinvar ↗
PP2 Available evidence does not establish that ASXL1 missense variation is a common disease mechanism with a low rate of benign missense variation, so PP2 was not applied. Details ▾Hide ▴
Evidence considered
  • Gene-level evidence supports loss of function as a disease mechanism but does not by itself justify PP2
Still missing
  • No gene-specific missense constraint or mechanism summary supporting PP2 was identified.
Sources
pvs1_gene_context
PP4 No individual-level phenotype data were identified to show a highly specific clinical presentation for a single genetic etiology. Details ▾Hide ▴
Still missing
  • No phenotype-rich case report was identified.
PP5 No reputable source classified this variant as pathogenic, and the available ClinVar entry is uncertain significance rather than a pathogenic assertion supporting PP5. Details ▾Hide ▴
Evidence considered
  • ClinVar uncertain significance
  • single submitter
Sources
clinvar ↗
BS2 No evidence was identified showing this variant in healthy adult individuals in a context sufficient to argue against disease causation. Details ▾Hide ▴
Evidence considered
  • Variant absent from reviewed population datasets
Still missing
  • No healthy carrier observations were identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional study was identified showing a normal or benign effect for this variant. Details ▾Hide ▴
Evidence considered
  • No variant-specific reviewed functional evidence identified
Still missing
  • No validated benign functional assay result specific to p.(Thr1268Ala) was identified.
Sources
oncokb ↗
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Still missing
  • No family study showing lack of segregation was identified.
BP1 ASXL1 loss of function is an established disease mechanism, but the currently reviewed evidence is not sufficient by itself to determine whether missense variation in this gene should be down-weighted under BP1 for this specific interpretation. Details ▾Hide ▴
Evidence considered
  • Gene-level loss-of-function mechanism supported
Still missing
  • No curated gene-specific missense-versus-truncating spectrum summary was identified for BP1 application.
Sources
pvs1_gene_context
BP2 No phase information was identified to show this variant in trans with a pathogenic variant for a dominant disorder or in cis for any relevant disorder context. Details ▾Hide ▴
Still missing
  • No cis/trans phase data were identified.
BP5 No evidence was identified that an alternate molecular cause fully explains an observed phenotype independent of this variant. Details ▾Hide ▴
Still missing
  • No individual-level alternate-diagnosis data were identified.
BP6 No reputable source classified this variant as benign or likely benign. The available ClinVar entry is uncertain significance. Details ▾Hide ▴
Evidence considered
  • ClinVar uncertain significance
  • single submitter
Sources
clinvar ↗
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PM4 N/AThis is a missense substitution and does not cause a protein length change, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence p.(Thr1268Ala)
BP3 N/AThis is not an in-frame deletion or insertion within a repetitive region, so BP3 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant consequence is missense
Sources
spliceai ↗

Identifiers

Gene
ASXL1
Transcript
NM_015338.5
Coding (HGVS c.)
NM_015338.5:c.3802A>G
Protein (HGVS p.)
NP_056153.2:p.(Thr1268Ala)
GRCh38
chr20:32436514 A>G
GRCh37
chr20:31024317 A>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…
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 SupportingMultiple computational results support a benign effect. REVEL is 0.098, BayesDel is -0.440581, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
  • REVEL 0.098
  • BayesDel -0.440581
  • SpliceAI max delta 0.00
Sources
revelbayesdelspliceai ↗
PP3 Available computational evidence does not support a damaging effect. REVEL is 0.098, BayesDel is -0.440581, and SpliceAI shows no predicted splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
  • REVEL 0.098
  • BayesDel -0.440581
  • SpliceAI max delta 0.00
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant consequence is missense
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.098. BayesDel score = -0.440581.

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

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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.098. BayesDel score = -0.440581.

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; COSV100038139, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.