The U2AF1 NM_006758.3:c.101C>T (NP_006749.1:p.(Ser34Phe)) missense variant has previously been reported in somatic cancers (COSMIC; COSV52341059, n = 340 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Independent cell, biochemical, minigene, and mouse studies consistently show U2AF1 S34F causes abnormal splicing and related cellular dysfunction. Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.U2AF1 encodes a small subunit of the U2 auxiliary factor, a protein complex essential for recognizing pre-mRNA splice sites and removing introns to produce mature messenger RNA. Alterations in U2AF1 are associated with myelodysplastic syndromes, acute myeloid leukemia, and chronic myelomonocytic leukemia. U2AF1 functions as an oncogene in cancer, where recurrent alterations can disrupt RNA splicing and contribute to the development and progression of myeloid malignancies.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, strong: independent cell, biochemical, minigene, and mouse studies consistently show U2AF1 S34F causes abnormal splicing and related cellular dysfunction.
Met at supporting strength: AF is 3.56e-6 in gnomAD v2.1 and 0 in v4.1, both below the <=0.0001 PM2 threshold.
Met at supporting strength: missense REVEL score 0.7 meets the >=0.644 PP3 threshold.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS3 strong plus PM2 and PP3 supporting satisfy the generic ACMG/AMP fallback rule of one strong plus two supporting criteria.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 0 / 18,936 alleles. Recorded AF 0. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 3.55548e-06; MAF= 0.00036%, 1/281256 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.01381e-05; MAF= 0.00401%, 1/24914 alleles, homozygotes = 0).
This variant is present in gnomAD-Canada v1.0 (AF= 0.0, 0/452 alleles, homozygotes = 0).
Recorded REVEL score: 0.700. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, single submitter.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV52341059, n = 340 times).
This variant lies in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 8 not met · 13 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Generic ACMG/AMP rules govern because no U2AF1 VCEP or CSPEC was available.
PS4 was not assessed because the available case frequency lacks a matched unaffected-control comparator and therefore cannot support the required OR >5.0 with a confidence interval excluding 1.0.
PP4 was not met because the reported hematologic phenotypes are not highly specific for a single genetic etiology.
PP5 and BP6 were not met because the exact-variant ClinVar record is single-submitter Oncogenic with no expert-panel Pathogenic/Likely pathogenic or Benign/Likely benign classification.
BP5 was not assessed because the reviewed evidence does not document an alternate molecular basis for disease in a patient carrying U2AF1 c.101C>T.
Generic ACMG/AMP rules govern because no VCEP covers U2AF1.
The missense consequence selects the REVEL path exclusively: REVEL 0.7 supports PP3 at supporting strength, while it does not meet BP4.
Population data support PM2 at Supporting strength: the variant is absent in gnomAD v4.1 and observed once at AF 3.555479705321842e-06 in gnomAD v2.1.
BA1 and BS1 cannot be formally assessed under the required grpmax FAF approach because grpmax FAF is null in both available gnomAD records; their point estimates do not approach the relevant thresholds.
BS2 cannot be assessed from zero homozygotes alone because no qualifying healthy-adult observation or inherited disease penetrance model is documented.
No criteria match.
PS3 is met at strong strength. The exact U2AF1 p.Ser34Phe variant was evaluated in multiple independent functional systems. PMID:22158538 used double-reporter and GH1 minigene assays in 293T cells and showed increased splicing efficiency and exon skipping versus wild type. PMID:25311244 demonstrated altered pre-mRNA splicing in primary human CD34+ cells, altered RNA-binding preference in purified U2AF1/U2AF2/SF1 complexes, and concordant GH1/FMR1 minigene effects. PMID:25267526 showed allele-specific changes in 3′ splice-site recognition with mutation-dependent minigene and in vitro splicing effects. PMID:25965570 demonstrated altered hematopoiesis and widespread differential splicing in a doxycycline-inducible human U2AF1(S34F) mouse model. PMID:30054334 showed increased R-loop accumulation, ATR response, DNA damage, apoptosis, and reduced viability in mutant-expressing cells, including primary CD34+ cells. PMID:30842218 used isogenic gene-edited cells and allele-disruption rescue to demonstrate mutant-dependent translational dysregulation and altered cellular responses. Together, the variant-specific, orthogonal assays, primary-cell and in-vivo models, wild-type comparators, and rescue/control designs provide well-established evidence of a damaging functional effect on U2AF1 and its splicing-related product function.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PM2 Supporting is met under the supplied generic threshold because the variant is absent from gnomAD v4.1 (0/18936 alleles) and is present only once in gnomAD v2.1 (1/281256; AF 3.555479705321842e-06), which is below the supplied <=0.0001 threshold. No governing VCEP requires a non-cancer or exome-only subset for this case, and no homozygotes are reported.
PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The variant is a missense SNV, NM_006758.3:c.101C>T (NP_006749.1:p.(S34F)), so the governing generic rule requires the missense REVEL path only; splice prediction is not used for PP3/BP4 in this situation. REVEL is 0.7, which meets the generic ClinGen SVI supporting PP3 threshold of >= 0.644 (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established.
PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is NP_006749.1:p.(Ser34Phe). The reviewed literature reports recurrent somatic U2AF1 p.Ser34Phe, but no previously established pathogenic variant with the same amino-acid change was identified. The available ClinVar record is a single-submitter somatic oncogenic record, not an ACMG pathogenic expert-panel determination, so it does not establish PS1.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PMID:22158538 reports the alternate missense change p.Ser34Tyr at the same residue as p.Ser34Phe. However, the paper describes both as recurrent somatic mutations and does not establish p.Ser34Tyr as a pathogenic variant under ACMG/AMP. Therefore, the required pathogenic same-residue comparator is not demonstrated.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
PP4 requires a patient phenotype or family history highly specific for a disease with a single genetic etiology. The available case evidence concerns myelodysplastic syndrome and related hematologic malignancy contexts, which are not a highly specific phenotype with a single genetic etiology for U2AF1 c.101C>T. No disease-specific phenotype or family-history evidence meeting PP4 was provided.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5 requires a reputable source to report the variant as pathogenic when the evidence is unavailable for independent evaluation. The exact-variant ClinVar record is classified Oncogenic with criteria provided by a single submitter, not an expert panel, and the available audit contains no expert-panel Pathogenic or Likely pathogenic classification. OncoKB reports Likely Oncogenic, not an ACMG expert-panel Pathogenic/Likely pathogenic classification. Under the specified generic rule, PP5 is not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BS3 is not met. The reviewed variant-specific functional studies do not show no damaging effect on protein function or splicing; instead, they consistently report abnormal splicing, altered splice-site recognition, altered hematopoiesis, R-loop-associated cellular stress, and mutant-dependent translational effects for U2AF1 S34F. No validated assay demonstrating preserved U2AF1 function or normal splicing for this variant was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The available gene-level evidence emphasizes recurrent U2AF1 missense substitutions at S34 and Q157 in hematologic malignancies, with functional studies of S34F altering splice-site recognition and splicing. This does not support a gene for which primarily truncating variants are known to cause disease, so BP1 is not met.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is a missense SNV, so the governing generic rule requires the missense REVEL path only; the SpliceAI result cannot be substituted for an indeterminate missense REVEL result. REVEL is 0.7, which is above the generic BP4 supporting cutoff of <= 0.29 and therefore does not support BP4. BayesDel is not used because no generic ACMG-strength calibration is established.
BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP6 requires a reputable source to report the variant as benign when the evidence is unavailable for independent evaluation. The exact-variant ClinVar record is Oncogenic with criteria provided by a single submitter, not an expert panel; no exact-variant ClinVar expert-panel Benign or Likely benign classification is available. Therefore BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No case-level evidence documents that U2AF1 c.101C>T (p.Ser34Phe) occurred de novo in an affected proband. The available records provide no maternity confirmation, paternity confirmation, or family-history assessment, so the PS2 definition cannot be evaluated.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
ACMG/AMP PS4 requires significantly increased prevalence in affected individuals compared with controls; the governing note requires RR or OR >5.0 with a confidence interval that does not include 1.0. PMID:22158538 reports U2AF1 p.Ser34Phe in 11 of 150 individuals with de novo MDS, but it does not report unaffected controls. The available gnomAD observations are population data without a matched case ancestry or a comparable somatic-case design, so a valid case-control OR and 95% CI cannot be established. The literature_pass PS4-indexed PMID:34131312 is a general somatic-variant standards paper whose available abstract does not provide variant-specific case-control counts for U2AF1 c.101C>T. Therefore PS4 is not assessed rather than inferred from the case-only frequency.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
The variant is at residue 34, which literature places in the first zinc finger of U2AF1 and a paper describes as a functionally relevant region. However, no VCEP domain table is available, no complete approved critical-domain list exists for U2AF1, and the available evidence does not establish absence of benign variation throughout that domain. The case also reports a statistically significant cancer hotspot, but the governing instructions restrict use of a somatic hotspot toward PM1 to a VCEP-named hotspot route; no VCEP covers U2AF1.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM3 cannot be assessed because the available evidence concerns the somatic U2AF1 p.S34F cancer-associated variant and provides no recessive disease context, affected-proband observation, pathogenic variant in the same individual, or parent/offspring testing establishing phase in trans. The available studies describe functional assays and somatic cancer cohorts rather than germline compound-heterozygous or biallelic disease observations.
For recessive disorders, detected in trans with a pathogenic variant
No case-level evidence documents an assumed de novo occurrence of U2AF1 c.101C>T (p.Ser34Phe) in an affected proband. There is no reported proband-parent testing or clinical family-history evidence from which an assumed de novo event could be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, informative meioses, genotype results, or phenotype-segregation assessments are documented for U2AF1 c.101C>T (p.Ser34Phe). Therefore, co-segregation with disease and any possible increased strength from multiple affected relatives cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The available sources document recurrent U2AF1 missense mutations, especially at S34, and functional consequences of S34F, but they do not establish both required gene-level conditions: a low rate of benign missense variation and missense variants as a common mechanism of disease in the applicable germline disease context. No validated gene-wide missense constraint or benign-missense-rate threshold is supplied.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
BA1 is not assessed because the required filtering metric, grpmax FAF, is null in both available gnomAD records. The available all-comers observations are far below the 5% threshold (gnomAD v2.1: 1/281256 alleles, AF 3.55548e-06; gnomAD v4.1: 0/18936), but the mandated FAF-based rule cannot be formally applied from these records. No non-cancer or exome-only governing specification is present, and no population frequency approaches the stand-alone benign threshold.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not assessed because the required filtering metric, grpmax FAF, is null in both available gnomAD records, and no disorder-specific maximum credible allele frequency can be calculated from the supplied evidence because prevalence, penetrance, and allelic heterogeneity for an inherited U2AF1 disorder are not established. The observed all-comers frequencies (3.55548e-06 in gnomAD v2.1 and 0 in gnomAD v4.1) are far below the generic 1% default, but the mandated FAF-based frequency assessment and disorder-specific comparison remain unavailable. The African/African American point estimate is only 1/24914 alleles and is not used as a substitute for grpmax FAF.
Allele frequency is greater than expected for the disorder.
BS2 is not assessed. gnomAD reports zero homozygotes in v2.1 and v4.1, but population counts do not document a healthy adult individual carrying the variant, the relevant zygosity, age, phenotype, or full penetrance of an early-onset disorder. The supplied case evidence concerns a somatic U2AF1 cancer variant and does not establish an inherited disease model or qualifying healthy-adult observation.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No affected family members carrying or lacking U2AF1 c.101C>T (p.Ser34Phe) are documented, and no phenotype-confirmed non-segregating relatives are described. Lack of segregation therefore cannot be established or distinguished from phenocopy, incomplete ascertainment, or another familial cause.
Lack of segregation in affected members of a family.
BP2 cannot be assessed because no affected-proband or family genotype data establish U2AF1 p.S34F in trans with a pathogenic variant in a fully penetrant dominant disorder, or in cis with a pathogenic variant under any inheritance pattern. The available evidence is from somatic cancer cohorts and functional cell studies and does not provide phase information.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
BP5 requires the variant to be found in a case with an alternate molecular basis for disease. The reviewed evidence establishes that U2AF1 p.Ser34Phe occurs in MDS and provides functional data, but it does not document an individual case in which a separate molecular diagnosis explains the disease. BP5 is not assessed because the required alternate molecular basis is not available in the cited evidence.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_006758.3:c.101C>T in U2AF1 is a missense substitution predicted to produce NP_006749.1:p.(Ser34Phe). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for U2AF1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_006758.3:c.101C>T in U2AF1 is a missense substitution predicted to produce NP_006749.1:p.(Ser34Phe). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for U2AF1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_006758.3:c.101C>T in U2AF1 is a missense substitution predicted to produce NP_006749.1:p.(Ser34Phe). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for U2AF1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006758.3:c.101C>T in U2AF1 is a missense substitution predicted to produce NP_006749.1:p.(Ser34Phe). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for U2AF1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in U2AF1, mapped onto the exon structure of NM_006758.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| African/African American1 / 24,914 | 4e-05 |
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/18936 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/704 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 3.55548e-06; MAF= 0.00036%, 1/281256 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.01381e-05; MAF= 0.00401%, 1/24914 alleles, homozygotes = 0).
This variant is present in gnomAD-Canada v1.0 (AF= 0.0, 0/452 alleles, homozygotes = 0).
The variant is a missense SNV, NM_006758.3:c.101C>T (NP_006749.1:p.(S34F)), so the governing generic rule requires the missense REVEL path only; splice prediction is not used for PP3/BP4 in this situation. REVEL is 0.7, which meets the generic ClinGen SVI supporting PP3 threshold of >= 0.644 (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established.
PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense SNV, so the governing generic rule requires the missense REVEL path only; the SpliceAI result cannot be substituted for an indeterminate missense REVEL result. REVEL is 0.7, which is above the generic BP4 supporting cutoff of <= 0.29 and therefore does not support BP4. BayesDel is not used because no generic ACMG-strength calibration is established.
BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006758.3:c.101C>T in U2AF1 is a missense substitution predicted to produce NP_006749.1:p.(Ser34Phe). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for U2AF1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.7. BayesDel score = 0.415417.
9 paper records listed. 6 cited in the classification.
The same nucleotide was mutated in all samples, resulting in either a p.Ser34Phe (n = 11) or p.Ser34Tyr (n = 2) substitution.
Location Results, recurrent U2AF1 mutations and functional assays; Figure 3 and Table 1
Context Sanger sequencing of U2AF1 in 150 individuals with de novo MDS; deep sequencing of genomic DNA and cDNA; double-reporter splicing and GH1 minigene exon-skipping assays in 293T cells.
The S34F and S34Y mutations, affecting the first zinc finger, were associated with nearly identical alterations at the −3 position in all six S34 mutant samples, whereas the Q157P mutation, affecting the second zinc finger, was associated with alterations at the +1 position.
Location Results, U2AF1 mutation-dependent sequence preferences; Figure 4A–B and Figure 5A
Context TCGA AML transcriptomes; engineered K562 cell lines expressing WT or mutant U2AF1; RNA-seq, alternative-splicing analysis, minigene assays, and in vitro splicing assays.
We found that U2AF1 (S34F) affects pre-mRNA splicing of a large number of target genes, some of which are known oncogenic drivers, and preferentially skips splice acceptor sites immediately adjacent to uridine at the −3 position.
Location Results, The S34F mutation affects pre-mRNA splicing; The S34F mutation alters the affinity of pre-mRNA to U2AF1; Specific effects of U2AF1 mutations in alternative splicing
Context RNA-seq and splice-junction analysis in primary human CD34+ cells; purified U2AF1/U2AF2/SF1 RNA-binding assays; GH1 and FMR1 minigene assays in 293T cells; RT-PCR validation.
We identified 8 samples with a spliceosome gene mutation, including 6 samples with a U2AF1 mutation affecting the S34 amino acid (4 S34F, 2 S34Y), 1 sample with U2AF1(Q157P), 1 sample with SF3B1(K700E), and 102 samples without a mutation or copy number alteration in spliceosome genes (Table S1).
Location Results, Splicing is altered in primary human AML cells expressing mutant U2AF1; Generation of U2AF1(S34F) transgenic mice
Context TCGA AML cohort; doxycycline-inducible human U2AF1(S34F) transgenic mice with bone-marrow transplantation, flow cytometry, competitive repopulation, and RNA sequencing.
Here we show that RNA splicing perturbation by expression of the U2AF1(S34F) mutant causes accumulation of R loops, a transcription intermediate containing RNA:DNA hybrids and displaced single-stranded DNA, and elicits an ATR response.
Location Abstract; Results, Expression of U2AF1S34F induces an R loop-associated ATR response; U2AF1S34F and other MDS-associated spliceosome mutants sensitize cells to ATRi
Context Engineered HeLa, K562, and OCI-AML3 cells and lentivirally transduced primary human CD34+ progenitors; R-loop, RPA-phosphorylation, γH2AX, viability, and apoptosis assays with ATR or ATM inhibitors.
This splicing-independent role of U2AF1 is altered by the S34F mutation, and polysome profiling indicates that the mutation affects translation of hundreds of mRNA.
Location Abstract; Results, U2AF1-S34F mutation confers altered viability and sustained inflammatory cytokine secretion after DNA damage; A noncanonical function for U2AF1 as a translational repressor
Context Isogenic gene-edited HBEC lines comparing wild type, heterozygous S34F, and mutant-allele-disrupted cells; validation in A549, H441, and NKM1 lines; RNA-seq, ELISA, immunoprecipitation/RT-qPCR, RIP-seq, polysome profiling, PAR-CLIP, and reporter assays.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/18936 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/704 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 3.55548e-06; MAF= 0.00036%, 1/281256 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.01381e-05; MAF= 0.00401%, 1/24914 alleles, homozygotes = 0).
This variant is present in gnomAD-Canada v1.0 (AF= 0.0, 0/452 alleles, homozygotes = 0).
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 4539541)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.7. BayesDel score = 0.415417.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52341059, n = 340 times).
This variant lies in a statistically significant hotspot.