LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-05
Case ID: NM_006758.3_c.470A_C_20261105_201749
Framework: ACMG/AMP 2015
Variant classification summary

NM_006758.3:c.470A>C

U2AF1  · NP_006749.1:p.(Gln157Pro)  · NM_006758.3
GRCh37: chr21:44514777 T>G  ·  GRCh38: chr21:43094667 T>G
Gene: U2AF1 Transcript: NM_006758.3
Final call
VUS
PS3 supporting PM1 moderate PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
U2AF1
Transcript
NM_006758.3
Protein
NP_006749.1:p.(Gln157Pro)
gnomAD AF
3.556890487293997e-05 (v4.1)
ClinVar
Likely pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 supporting: Q157P altered splicing and increased ATR-inhibition-induced gamma-H2AX in controlled cellular assays.
2
PM1 moderate: Q157P lies at the recurrent U2AF1 Q157 mutational hotspot.
3
PM2 supporting: gnomAD v4.1 filtering allele frequency is 3.085e-05, below the 0.0001 threshold, with zero homozygotes.
Final determination: Under the generic ACMG/AMP 2015 fallback, one moderate criterion plus two supporting criteria does not meet any pathogenic, likely pathogenic, benign, or likely benign combination rule, so the call is VUS.
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 N/A Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: no previously established pathogenic Gln157Pro substitution caused by a different nucleotide change was identified.
clinvar PMID:25267526 PMID:25311244 PMID:30054334 PMID:33122737
PS2 Not assessed Not assessed: no case-level evidence documents confirmed maternity, confirmed paternity, and absence of family history for this variant.
PMID:25267526 PMID:25311244 PMID:30054334 PMID:33122737
PS3 Met Met at supporting strength: Q157P altered splicing in K562 and 293T assays and increased ATR-inhibition-induced gamma-H2AX in HeLa cells versus wild-type controls.
PMID:25267526 PMID:25311244 PMID:30054334
PS4 Not assessed Not assessed: Q157P occurred in 7/234 MDS patients, but no matched control counts support the required OR >5.0 and confidence interval excluding 1.0.
PMID:33122737 gnomad_v4
PM1 Met Met: p.Gln157Pro lies at Q157, reported as a statistically significant Cancer Hotspots hotspot, although the extracted hotspot row requires human confirmation.
hotspots PMID:25267526 PMID:25311244 PMID:33122737
PM2 Met Met at supporting strength: gnomAD v4.1 grpmax FAF is 3.085e-05, below the generic PM2 threshold of 0.0001, with zero homozygotes.
gnomad_v2 gnomad_v4 PMID:25741868
PM3 Not assessed Not assessed: no affected-proband observation, pathogenic allele, or parental/offspring phase testing demonstrates this variant in trans.
clinvar PMID:25311244 PMID:33122737
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: Q157R is reported at residue 157, but a qualifying prior determination that Q157R is pathogenic is not supplied.
PMID:25267526 PMID:25311244 PMID:33122737 pm5_candidates
PM6 Not assessed Not assessed: no disease-affected proband is documented with an assumed de novo variant and unconfirmed parental origin.
PMID:25267526 PMID:25311244 PMID:30054334 PMID:33122737
PP1 Not assessed Not assessed: no family-level segregation data show this variant co-segregating with disease in multiple affected relatives.
PMID:25267526 PMID:25311244 PMID:30054334 PMID:33122737
PP2 Not assessed Not assessed: gene-level evidence for both low benign missense variation and a common missense disease mechanism is not supplied.
PMID:25267526 PMID:25311244 PMID:33122737
PP3 Not met Not met: missense REVEL 0.555 is below the >=0.644 PP3 supporting threshold.
revel
PP4 Not met Not met: available evidence documents somatic MDS mutation cohorts and assays, not a highly specific patient phenotype or family history for one genetic disease.
PMID:33122737 clinvar
PP5 Not met Not met: ClinVar has one exact-variant Likely pathogenic single-submitter record and zero expert-panel submissions, so PP5 is not triggered.
clinvar
BA1 Not met Not met: gnomAD grpmax FAF is 3.085e-05 at most, far below the 0.05 BA1 threshold in populations with over 2000 observed alleles.
gnomad_v2 gnomad_v4 PMID:25741868
BS1 Not met Not met: the highest applicable gnomAD grpmax FAF is 3.085e-05, far below the generic 0.01 BS1 threshold.
gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: zero gnomAD homozygotes does not establish a healthy-adult observation or the full-penetrance inheritance context required for BS2.
gnomad_v2 gnomad_v4 clinvar
BS3 Not met Not met: Q157P altered splicing and increased ATR-inhibition-induced gamma-H2AX versus wild-type controls, rather than showing no damaging effect on U2AF1 function.
PMID:25267526 PMID:25311244 PMID:30054334
BS4 Not assessed Not assessed: no affected relatives with documented negative variant testing establish lack of segregation.
PMID:25267526 PMID:25311244 PMID:30054334 PMID:33122737
BP1 Not assessed Not assessed: the supplied evidence does not establish whether U2AF1 disease is primarily caused by truncating variants.
PMID:25267526 PMID:25311244 PMID:30054334 PMID:33122737
BP2 Not assessed Not assessed: no phase-resolved observation shows this variant in trans or cis with a pathogenic variant in an affected individual.
clinvar PMID:25311244 PMID:33122737
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: missense REVEL 0.555 exceeds the <=0.29 BP4 supporting threshold and is indeterminate.
revel
BP5 Not assessed Not assessed: one MDS patient had Q157P and S34F, but the evidence does not establish S34F as the alternate molecular basis of disease.
PMID:33122737
BP6 Not met Not met: ClinVar has no exact-variant Benign or Likely benign expert-panel assertion and instead contains one Likely pathogenic single-submitter record.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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