ASXL1 c.3379G>A, p.Asp1127Asn
NM_015338.5:c.3379G>A
COSMIC ID: COSM110714, COSM7078974
Variant of Uncertain Significance (VUS)
The variant NM_015338.5:c.3379G>A (p.D1127N) in ASXL1 is classified as a Variant of Uncertain Significance due to the presence of moderate pathogenic evidence (PM2) and supporting benign evidence (BP1, BP4) that are conflicting, with insufficient additional data to resolve its clinical impact.
ACMG/AMP Criteria Applied
PM2
BP1
BP4
Genetic Information
Gene & Transcript Details
Gene
ASXL1
Transcript
NM_015338.6
MANE Select
Total Exons
13
Strand
Forward (+)
Reference Sequence
NC_000020.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_015338.5 | RefSeq Select | 13 exons | Forward |
| NM_015338.4 | Alternative | 13 exons | Forward |
| NM_015338.3 | Alternative | 13 exons | Forward |
Variant Details
HGVS Notation
NM_015338.5:c.3379G>A
Protein Change
D1127N
Location
Exon 13
(Exon 13 of 13)
5'Exon Structure (13 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1127 in gene ASXL1
Alternate Identifiers
COSM110714, COSM7078974
Variant interpretation based on transcript NM_015338.6
Genome Browser
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HGVS InputNM_015338:c.3379G>A
Active Tracks
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Clinical Data
Global Frequency
0.0124%
Low Frequency
Highest in Population
European (non-Finnish)
0.0201%
Low Frequency
Global: 0.0124%
European (non-Finnish): 0.0201%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282872Alt: 35Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0124%, 35/282872 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.0201%, 26/129188 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
1 VUS
1 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Benign (1 clinical laboratories) and as Likely benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 1127 in gene ASXL1
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.013
0.013
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.30polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: it is a missense change (D1127N), not a null variant. Therefore, this criterion is not applied at Not Applied strength because it does not meet the definition of a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: no previously established pathogenic variant with the same amino acid change at position 1127. Therefore, this criterion is not applied at Not Applied strength because there is no matching pathogenic amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no parental testing data available to confirm de novo status. Therefore, this criterion is not applied at Not Applied strength because de novo confirmation is lacking.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional data are unavailable.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or cohort data demonstrating enrichment in affected individuals. Therefore, this criterion is not applied at Not Applied strength because there is no statistical evidence of increased prevalence.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: position 1127 is not reported as a mutational hotspot or critical domain. Therefore, this criterion is not applied at Not Applied strength because it does not reside in a known hotspot or functional domain.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: MAF = 0.0124% in gnomAD (35/282,872 alleles), which is below the 0.1% threshold. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no information on trans configuration with another variant. Therefore, this criterion is not applied at Not Applied strength because phase and zygosity data are missing.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a single amino acid substitution with no change in protein length. Therefore, this criterion is not applied at Not Applied strength because it does not alter protein length.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no pathogenic missense changes reported at residue 1127. Therefore, this criterion is not applied at Not Applied strength because no other pathogenic variant has been seen at this residue.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no data on assumed de novo status. Therefore, this criterion is not applied at Not Applied strength because there is no de novo evidence.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data available. Therefore, this criterion is not applied at Not Applied strength because segregation analysis is lacking.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: insufficient evidence regarding ASXL1 missense constraint and mechanism. Therefore, this criterion is not applied at Not Applied strength because the gene’s missense constraint is not established.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product". The evidence for this variant shows: computational tools predict benign impact (REVEL 0.01, CADD, PolyPhen). Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or clinical data provided. Therefore, this criterion is not applied at Not Applied strength because phenotype data are missing.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: ClinVar entries are conflicting (VUS, Benign, Likely Benign). Therefore, this criterion is not applied at Not Applied strength because there is no consistent reputable pathogenic report.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF = 0.0124%, well below the >5% threshold. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not high enough.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: MAF = 0.0124%, with no known threshold for ASXL1. Therefore, this criterion is not applied at Not Applied strength because frequency is not demonstrably higher than expected.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age". The evidence for this variant shows: presence in gnomAD, but health status and age are unknown. Therefore, this criterion is not applied at Not Applied strength because healthy adult confirmation is lacking.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied at Not Applied strength because functional evidence is lacking.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no family data to assess segregation. Therefore, this criterion is not applied at Not Applied strength because segregation data are unavailable.
BP1
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss of function causes disease". The evidence for this variant shows: ASXL1-related disorders are caused by truncating (LoF) variants, and this is a missense change. Therefore, this criterion is applied at Supporting strength because this missense variant occurs in a gene where only LoF is known to be pathogenic.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no data on occurrence with other variants. Therefore, this criterion is not applied at Not Applied strength because allelic configuration is unknown.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because it is not an indel.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: REVEL score 0.01 (below 0.15), benign predictions from CADD and PolyPhen, and SpliceAI score 0.01 indicating no splicing impact. Therefore, this criterion is applied at Supporting strength because computational analyses consistently predict no deleterious effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no case reports with another molecular cause. Therefore, this criterion is not applied at Not Applied strength because no alternate molecular basis is documented.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: ClinVar entries include benign classifications but with accessible evidence. Therefore, this criterion is not applied at Not Applied strength because there is no unverified benign report.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a missense substitution, not synonymous. Therefore, this criterion is not applied at Not Applied strength because it is not a synonymous variant.