NM_015338.5:c.2694G>A

ASXL1 · NP_056153.2:p.(Trp898Ter) · NM_015338.5

GRCh37: chr20:31023209 G>A · GRCh38: chr20:32435406 G>A

Gene: ASXL1 Transcript: NM_015338.5

Final call

VUS

PVS1 moderate PM2 supporting

Variant details

Gene

ASXL1

Transcript

NM_015338.5

Protein

NP_056153.2:p.(Trp898Ter)

gnomAD AF

1.239105167812013e-06 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_015338.5:c.2694G>A (p.Trp898Ter) is a nonsense variant in exon 13 of 13 in ASXL1, a gene for which loss of function is an established disease mechanism.

Under ClinGen SVI PVS1 recommendations (PMC6185798), the variant is located in the terminal exon and is not expected to undergo nonsense-mediated decay; PVS1 is applied at moderate strength.

The variant is extremely rare in population databases with an allele frequency of 3.98 × 10⁻⁶ in gnomAD v2.1 and 1.24 × 10⁻⁶ in gnomAD v4.1, meeting PM2 at supporting level.

No additional pathogenic or benign criteria were met; the variant is absent from ClinVar, no variant-specific functional studies exist, and no segregation or de novo data are available.

Based on generic ACMG/AMP 2015 combination rules, one moderate criterion (PVS1_Moderate) and one supporting criterion (PM2_Supporting) are met, yielding a classification of Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	NM_015338.5:c.2694G>A is a nonsense variant predicted to introduce a premature termination codon at residue 898 (p.Trp898Ter). ASXL1 loss of function is an established disease mechanism for Bohring-Opitz syndrome (germline) and myeloid malignancies. Under ClinGen SVI PVS1 recommendations (PMC6185798), nonsense variants in the last exon are not expected to undergo NMD and are downgraded. This variant resides in exon 13 (the final exon) and removes the C-terminal 644 amino acids of the 1542-residue protein; the functional significance of the truncated region is uncertain, warranting PVS1 at moderate strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No alternative nucleotide change producing the same p.Trp898Ter amino acid alteration has been reported as pathogenic. ClinVar contains no entry for this variant or any other W898* variant.	clinvar
PS2	Not met	No de novo occurrence of NM_015338.5:c.2694G>A has been reported in any patient. No published case report or ClinVar submission documents a de novo observation of this variant.	clinvar
PS3	Not met	No well-established functional studies directly assess the biological effect of the specific p.Trp898Ter variant. Five publications discuss ASXL1 truncations in general and support loss-of-function as a disease mechanism in somatic myeloid malignancies, but none experimentally characterize NM_015338.5:c.2694G>A.
PS4	Not met	No case-control study or statistically significant enrichment of NM_015338.5:c.2694G>A in affected individuals compared to population controls has been reported. The variant is absent from ClinVar and no proband counts are available.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	No reputable source (ClinVar, clinical laboratory, or expert panel) has classified NM_015338.5:c.2694G>A as pathogenic. The variant is absent from ClinVar entirely. OncoKB annotates the variant as Likely Oncogenic in a somatic context, which does not constitute a germline classification.	clinvar oncokb
PM1	Not met	NM_015338.5:c.2694G>A (p.Trp898Ter) does not lie within a statistically significant mutational hotspot. Although ASXL1 truncating mutations cluster broadly across exons 12–13, residue 898 is not a recurrently mutated codon in the hotspot analysis.	clinvar
PM2	Met	NM_015338.5:c.2694G>A is extremely rare in population databases, with an allele frequency far below the 0.1% PM2 threshold. gnomAD v2.1 reports 1 allele in 251,448 (AF = 3.98 × 10⁻⁶) and gnomAD v4.1 reports 2 alleles in 1,614,068 (AF = 1.24 × 10⁻⁶), with zero homozygotes in both datasets.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a pathogenic missense variant at the same codon. NM_015338.5:c.2694G>A is a nonsense variant, and no same-residue comparator variants were identified in ClinVar.	pm5_candidates
PM6	Not met	No de novo observation of NM_015338.5:c.2694G>A has been reported, with or without confirmation of paternity and maternity.	clinvar
PP1	Not met	No segregation data are available for NM_015338.5:c.2694G>A in affected families.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. NM_015338.5:c.2694G>A is a nonsense (truncating) variant, not a missense variant.
PP3	Not met	In silico evidence for a deleterious effect is limited and does not meet the PP3 threshold requiring multiple independent lines of computational support. SpliceAI predicts no splicing impact (max delta = 0.01). BayesDel scores 0.66, marginally above the 0.5 threshold, but REVEL and HCI prior scores are unavailable for this variant. A single borderline in silico predictor is insufficient to invoke PP3.	spliceai bayesdel
PP4	Not met	No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for an ASXL1-related disorder.
PP5	Not met	No reputable germline source (ClinVar, clinical diagnostic laboratory, or expert panel) has classified NM_015338.5:c.2694G>A as pathogenic. The OncoKB annotation of Likely Oncogenic applies to a somatic cancer context and does not satisfy PP5 for germline variant interpretation.	clinvar oncokb
BA1	Not met	NM_015338.5:c.2694G>A has an allele frequency far below the 1% BA1 threshold. The highest population sub-frequency is 8.79 × 10⁻⁶ in gnomAD v2.1 European (non-Finnish).	gnomad_v2 gnomad_v4
BS1	Not met	NM_015338.5:c.2694G>A has an allele frequency far below the 0.3% BS1 threshold. The variant is observed in only 1–2 alleles across >1.8 million chromosomes in gnomAD.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available documenting that NM_015338.5:c.2694G>A has been observed in a healthy adult individual in a pattern inconsistent with the disease penetrance model (e.g., homozygous for a dominant disorder).
BS3	Not met	No well-established functional studies demonstrate that NM_015338.5:c.2694G>A (p.Trp898Ter) has no damaging effect on protein function or splicing.
BS4	Not met	No segregation data are available to assess non-segregation of NM_015338.5:c.2694G>A with disease in affected families.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are a known disease mechanism. NM_015338.5:c.2694G>A is itself a truncating (nonsense) variant, not a missense variant.
BP2	Not met	No data are available demonstrating that NM_015338.5:c.2694G>A has been observed in trans with a pathogenic variant for a dominant disorder, or in cis with a known pathogenic variant for a recessive disorder.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_015338.5:c.2694G>A is a single-nucleotide substitution, not an in-frame indel.
BP4	Not met	Multiple lines of computational evidence do not convincingly suggest a benign impact. While SpliceAI predicts no splicing alteration (delta = 0.01), BayesDel scores 0.66, which is above the 0.5 threshold favoring a deleterious interpretation. The in silico evidence is conflicting rather than consistently benign.	spliceai bayesdel
BP5	Not met	No data are available indicating that NM_015338.5:c.2694G>A has been observed in a case where an alternative molecular cause for disease was identified.
BP6	Not met	No reputable source has classified NM_015338.5:c.2694G>A as benign or likely benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous variants without predicted splice impact. NM_015338.5:c.2694G>A is a nonsense variant, not a synonymous variant.

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