ASXL1 c.3559G>A, p.Gly1187Ser
NM_015338.5:c.3559G>A
Variant of Uncertain Significance (VUS)
This variant is classified as a Variant of Uncertain Significance because it is absent from population databases (PM2) and computational evidence supports no impact (BP4), but there is insufficient additional evidence (functional data, segregation, de novo status, case-control studies) to support a pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM2
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.3559G>A
Protein Change
G1187S
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 1187 in gene ASXL1
Variant interpretation based on transcript NM_015338.6
Genome Browser
Loading genome browser...
HGVS InputNM_015338:c.3559G>A
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
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 1187 in gene ASXL1
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.012
0.012
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'PVS1 – Null variant in a gene where loss of function (LoF) is a known mechanism of disease.' The evidence for this variant shows: This is a missense change (G1187S), not a predicted null variant. Therefore, this criterion is not applied because the variant is not a predicted loss-of-function.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change.' The evidence for this variant shows: No previously established pathogenic variant causes G1187S in ASXL1. Therefore, this criterion is not applied because there is no known pathogenic amino acid change at this residue.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows: No information on de novo status or parental testing. Therefore, this criterion is not applied because de novo status has not been established.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'PS3 – 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 for G1187S. Therefore, this criterion is not applied because functional impact has not been experimentally assessed.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'PS4 – Prevalence in affected individuals significantly increased compared with controls.' The evidence for this variant shows: No case-control or prevalence data in affected cohorts. Therefore, this criterion is not applied because there is no statistical enrichment in patients.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'PM1 – Located in a mutational hot spot or well-established functional domain without benign variation.' The evidence for this variant shows: No information on hotspot or functional domain relevance for residue 1187 in ASXL1. Therefore, this criterion is not applied because domain‐specific evidence is lacking.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'PM2 – Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: Variant not found in gnomAD or other population databases (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'PM3 – Detected in trans with a pathogenic variant (for recessive disorders).' The evidence for this variant shows: No evidence of trans configuration with another pathogenic allele. Therefore, this criterion is not applied because zygosity and trans status are unknown.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants.' The evidence for this variant shows: This is a missense substitution without change in protein length. Therefore, this criterion is not applied because there is no in-frame indel or stop-loss.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen.' The evidence for this variant shows: No other pathogenic missense variants reported at codon 1187. Therefore, this criterion is not applied because no pathogenic variant at this residue is known.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'PM6 – Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: No de novo data. Therefore, this criterion is not applied because parental confirmation is not available.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'PP1 – Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: No family segregation data. Therefore, this criterion is not applied because segregation studies are not available.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'PP2 – 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: ASXL1 has both missense and LoF variants; no specific constraint information provided. Therefore, this criterion is not applied due to insufficient evidence about missense constraint.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product.' The evidence for this variant shows: Computational tools (REVEL 0.01, SpliceAI 0) indicate benign impact. Therefore, this criterion is not applied because in silico evidence does not support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'PP4 – Patient’s phenotype or family history highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: No clinical phenotype or family history data provided. Therefore, this criterion is not applied because phenotype specificity is unknown.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'PP5 – Reputable source reports variant as pathogenic, but without accessible evidence.' The evidence for this variant shows: Not reported in ClinVar or other databases. Therefore, this criterion is not applied because no reputable source lists this variant as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'BA1 – Allele frequency is too high for the disorder (based on population data).' The evidence for this variant shows: MAF = 0%, well below the BA1 threshold. Therefore, this criterion is not applied because allele frequency is not high.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'BS1 – Allele frequency is greater than expected for the disorder.' The evidence for this variant shows: Absent from population databases. Therefore, this criterion is not applied because frequency is not greater than expected.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'BS2 – Observed in a healthy adult individual for a dominant disorder.' The evidence for this variant shows: No data on observation in healthy adults. Therefore, this criterion is not applied because there is no healthy individual data.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'BS3 – Well-established functional studies show no damaging effect on protein function or splicing.' The evidence for this variant shows: No functional assays performed. Therefore, this criterion is not applied because functional benign evidence is not available.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'BS4 – Lack of segregation in affected family members.' The evidence for this variant shows: No family segregation data. Therefore, this criterion is not applied because segregation has not been assessed.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'BP1 – Missense variant in a gene where only loss-of-function causes disease.' The evidence for this variant shows: ASXL1 disease mechanism includes both LoF and missense in some contexts. Therefore, this criterion is not applied because missense cannot be presumed benign.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant.' The evidence for this variant shows: No evidence of cis/trans configuration with other pathogenic variants. Therefore, this criterion is not applied because no such observations exist.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'BP3 – In-frame deletions/insertions in a repetitive region without known function.' The evidence for this variant shows: This is a missense change, not an in-frame indel. Therefore, this criterion is not applied because variant type does not match.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'BP4 – Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.).' The evidence for this variant shows: REVEL score = 0.01 (below 0.15) and SpliceAI = 0. Therefore, this criterion is applied at Supporting strength because in silico tools predict benign impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'BP5 – Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: No case with alternative molecular diagnosis reported. Therefore, this criterion is not applied because no such cases are documented.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'BP6 – Reputable source reports variant as benign, but without accessible evidence.' The evidence for this variant shows: Not reported as benign in any database. Therefore, this criterion is not applied because no reputable benign report exists.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'BP7 – Synonymous variant with no predicted impact on splicing.' The evidence for this variant shows: This is a missense variant, not synonymous. Therefore, this criterion is not applied because variant type does not match.