0%
U2AF1c.101C>TLikely pathogenic
Print report
Variant interpretation report

U2AF1 c.101C>T, p.(Ser34Phe)

NM_006758.2:c.101C>T NP_006749.1:p.(Ser34Phe) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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.

In plain language

Gene-level background from the recorded interpretation.

About U2AF1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 5 Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Strong
PS3 · strong

Well-established functional evidence demonstrates that U2AF1 S34F has a damaging gain-of-function effect: it alters 3′ splice site recognition, changes sequence specificity of pre-mRNA binding, causes aberrant exon skipping and alternative splicing of hundreds of genes, induces R-loop accumulation and ATR checkpoint activation, and produces altered hematopoiesis with leukopenia and progenitor expansion in transgenic mouse models.

PM1Moderate
PM1 · moderate

The variant is located at codon 34 in the first CCCH zinc finger domain (ZnF1) of U2AF1, a well-established mutational hotspot. Codon S34 is recurrently mutated (S34F, S34Y) in MDS and AML. The hotspot analysis confirms the residue is statistically significant. This domain is critical for RNA binding and 3′ splice site recognition.

PM2Supporting
PM2 · supporting

The variant is extremely rare in population databases. gnomAD v2.1 reports an allele frequency of 3.56×10⁻⁶ (1/281,256 alleles, no homozygotes), and gnomAD v4.1 reports 0/18,936 alleles. The highest subpopulation frequency is 4.01×10⁻⁵ in African/African American. This is well below the 0.1% PM2 threshold.

PP2Supporting
PP2 · supporting

U2AF1 has a low rate of benign missense variation in population databases and missense variants are a well-established disease mechanism. Pathogenic U2AF1 variants cluster in the zinc finger domains at specific residues (S34, Q157), and the gene shows constraint against missense variation.

PP3Supporting
PP3 · supporting

In silico predictors support a deleterious effect. REVEL score is 0.7 (above the 0.5 threshold for pathogenic prediction). SpliceAI predicts no splice impact (max delta 0.0), consistent with a missense effect rather than splicing defect. BayesDel score is 0.415 (borderline). Overall, REVEL provides supporting evidence for pathogenicity.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM1 moderate, PM2 supporting, PP2 supporting, PP3 supporting; combination = 1 strong + 1 moderate + 3 supporting, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
0 / 18,936 alleles

gnomAD v4.1: 0 / 18,936 alleles. Recorded AF 0. Recorded homozygote count 0.

gnomAD v2.1

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).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
340 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV52341059, n = 340 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 5 met · 4 not met · 14 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_006758.2:c.101C>T (p.Ser34Phe) in U2AF1 is classified as Likely Pathogenic using generic ACMG/AMP 2015 criteria (PMID:25741868) with 1 strong, 1 moderate, and 3 supporting pathogenic criteria.

Well-established functional studies demonstrate that the U2AF1 S34F substitution has a damaging gain-of-function effect: it alters 3′ splice site recognition, changes sequence specificity of pre-mRNA binding, promotes aberrant exon skipping, induces R-loop accumulation and ATR checkpoint activation, and produces altered hematopoiesis in transgenic mouse models (PS3_Strong).

The variant is located at codon 34 in the first CCCH zinc finger domain, a well-established mutational hotspot where recurrent somatic missense mutations (S34F, S34Y) are observed in myelodysplastic syndromes and acute myeloid leukemia (PM1_Moderate).

The variant is extremely rare in population databases: gnomAD v2.1 reports 1 allele in 281,256 (AF=3.56×10⁻⁶) and gnomAD v4.1 reports 0 alleles in 18,936, both well below the PM2 threshold of 0.1% (PM2_Supporting).

U2AF1 has a low rate of benign missense variation and missense variants at the zinc finger domains are the established disease mechanism, supporting PP2 at a supporting level (PP2_Supporting).

Multiple in silico predictors support a deleterious effect: REVEL score of 0.7 is above the pathogenic threshold; BayesDel (0.415) is borderline (PP3_Supporting).

No benign criteria were met. The variant is not a common polymorphism (BA1/BS1 not met), functional studies show a damaging effect (BS3 not met), and computational evidence does not support a benign interpretation (BP4 not met).

Limitations: all functional evidence is derived from somatic disease contexts (MDS/AML cell lines and patient samples); no germline-specific functional data, de novo reports, cosegregation data, or germline case-control data are available. PVS1, PS1, PS2, PS4, PS5, PM5, PM6, PP1, PP4, PP5, and most benign criteria were not assessed due to absent or insufficient evidence.

Met · 5

PS3 StrongWell-established functional evidence demonstrates that U2AF1 S34F has a damaging gain-of-function effect: it alters 3′ splice site recognition, changes sequence specificity of pre-mRNA binding, causes aberrant exon skipping and alternative splicing of hundreds of genes, induces R-loop accumulation and ATR checkpoint activation, and produces altered hematopoiesis with leukopenia and progenitor expansion in transgenic mouse models. Details ▾Hide ▴
Evidence considered
  • U2AF1 S34F alters 3′ splice site recognition in hematological malignancies
  • affecting hundreds of genes including DNMT3B
  • ATR
  • CASP8 (PMID:25267526).
  • S34F promotes enhanced splicing and exon skipping in double-reporter and minigene assays in 293T cells
  • recurrently mutated in 13/150 (8.7%) de novo MDS patients (PMID:22158538).
  • U2AF1 S34F alters sequence specificity of pre-mRNA binding and splicing
  • shift from T to C preference at the −3 position of the 3′ splice site (PMID:25311244).
  • Transgenic U2AF1(S34F) mice display altered hematopoiesis (leukopenia
  • progenitor expansion
  • altered lineage distribution) and pre-mRNA splicing changes in hematopoietic progenitor cells in vivo (PMID:25965570).
  • U2AF1 S34F causes R-loop accumulation and ATR response
  • ATR inhibition selectively kills S34F-expressing cells including primary human CD34+ hematopoietic progenitors (PMID:30054334).
Still missing
  • All functional evidence is derived from somatic/leukemia disease models
  • no germline-specific functional data available. The functional studies were performed in cancer cell lines (HeLa
  • K562
  • OCI-AML3
  • 293T) and somatic MDS/AML patient samples.
Sources
PMID:25267526 ↗PMID:22158538 ↗PMID:25311244 ↗PMID:25965570 ↗PMID:30054334 ↗
PM1 ModerateThe variant is located at codon 34 in the first CCCH zinc finger domain (ZnF1) of U2AF1, a well-established mutational hotspot. Codon S34 is recurrently mutated (S34F, S34Y) in MDS and AML. The hotspot analysis confirms the residue is statistically significant. This domain is critical for RNA binding and 3′ splice site recognition. Details ▾Hide ▴
Evidence considered
  • S34 is the most recurrently mutated codon in U2AF1 across hematological malignancies (PMID:22158538
  • PMID:25267526).
  • The ZnF1 domain is critical for RNA binding specificity
  • S34F/Y mutations alter 3′ splice site sequence preference (PMID:25311244).
  • Residue is statistically significant in hotspot analysis.
Sources
PMID:25267526 ↗PMID:22158538 ↗PMID:25311244 ↗PMID:25965570 ↗PMID:30054334 ↗
PM2 SupportingThe variant is extremely rare in population databases. gnomAD v2.1 reports an allele frequency of 3.56×10⁻⁶ (1/281,256 alleles, no homozygotes), and gnomAD v4.1 reports 0/18,936 alleles. The highest subpopulation frequency is 4.01×10⁻⁵ in African/African American. This is well below the 0.1% PM2 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=3.56×10⁻⁶ (1/281
  • 256 alleles)
  • max subpop AF=4.01×10⁻⁵ (AFR).
  • gnomAD v4.1: AF=0 (0/18
  • 936 alleles).
  • No homozygotes in any database.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP2 SupportingU2AF1 has a low rate of benign missense variation in population databases and missense variants are a well-established disease mechanism. Pathogenic U2AF1 variants cluster in the zinc finger domains at specific residues (S34, Q157), and the gene shows constraint against missense variation. Details ▾Hide ▴
Evidence considered
  • U2AF1 missense variants at S34 and Q157 are the established disease mechanism in MDS/AML.
  • Extremely low missense variation observed in gnomAD
  • only 1 allele across 281
  • 256 in v2.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP3 SupportingIn silico predictors support a deleterious effect. REVEL score is 0.7 (above the 0.5 threshold for pathogenic prediction). SpliceAI predicts no splice impact (max delta 0.0), consistent with a missense effect rather than splicing defect. BayesDel score is 0.415 (borderline). Overall, REVEL provides supporting evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.7 (pathogenic-leaning).
  • BayesDel: 0.415 (borderline
  • benign-leaning).
  • SpliceAI: max delta 0.0 (no splice impact predicted).
Still missing
  • HCI Prior not available for U2AF1. BayesDel is borderline.
Sources
revelbayesdelspliceai ↗

Not met · 4 · evaluated, threshold not reached

BA1 The variant allele frequency (3.56×10⁻⁶ in gnomAD v2.1, 0 in gnomAD v4.1) is far below the 1% BA1 threshold. Not a common benign polymorphism. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF: 3.56×10⁻⁶.
  • gnomAD v4.1 AF: 0.
  • Both far below 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant allele frequency is far below the 0.3% BS1 threshold. Not a common benign variant. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF: 3.56×10⁻⁶.
  • gnomAD v4.1 AF: 0.
  • Both far below 0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 Well-established functional studies consistently show a damaging gain-of-function effect, not a benign effect. U2AF1 S34F alters splicing, causes R-loop accumulation, and produces hematopoietic abnormalities across multiple independent studies. BS3 requires evidence of no damaging effect. Details ▾Hide ▴
Evidence considered
  • Functional studies consistently demonstrate a damaging gain-of-function splicing defect.
  • No well-established functional study shows a benign effect.
Sources
PMID:25267526 ↗PMID:22158538 ↗PMID:25965570 ↗
BP4 Multiple lines of computational evidence do not suggest a benign impact. REVEL score of 0.7 supports a deleterious effect, and BayesDel score of 0.415 is borderline. SpliceAI predicts no splicing impact (delta 0.0), but REVEL outweighs toward deleterious. BP4 requires consensus evidence of no impact. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.7 (deleterious).
  • BayesDel: 0.415 (borderline).
  • No consensus of benign computational prediction.
Sources
revelbayesdel

Not assessed · 14 · no assessment recorded

PS1 No evidence of an alternate nucleotide change producing the same amino acid substitution (p.Ser34Phe) was identified. Details ▾Hide ▴
Still missing
  • No same-amino-acid-by-different-nucleotide variant known.
PS2 No de novo case report confirming this variant as a confirmed de novo occurrence in a patient with disease was identified. Details ▾Hide ▴
Still missing
  • No de novo data available.
PS4 The variant is recurrently observed in somatic cancers (COSMIC n=340) but no germline case-control data demonstrating significantly increased prevalence in affected individuals versus controls is available. Details ▾Hide ▴
Evidence considered
  • COSMIC reports 340 somatic observations (COSV52341059).
  • No germline case-control prevalence data.
Still missing
  • No germline case-control data
  • somatic observations alone do not satisfy germline PS4.
PM5 A different pathogenic missense change (p.Ser34Tyr, S34Y) is established at the same residue, but the automated PM5 candidate pipeline could not confirm classic same-residue comparator semantics from ClinVar. Manual review of the literature confirms S34Y is recurrently reported as pathogenic alongside S34F; however, per pipeline guidance PM5 should not be applied from this artifact alone. Details ▾Hide ▴
Evidence considered
  • S34Y is described in multiple publications as a recurrent pathogenic variant at the same residue (PMID:22158538
  • PMID:25267526
  • PMID:25311244).
  • PM5 candidate pipeline recommends not_applicable
  • manual override deferred.
Still missing
  • PM5 candidate pipeline recommended not_applicable
  • human reviewer should determine if S34Y comparators satisfy PM5.
Sources
PMID:25267526 ↗PMID:22158538 ↗PMID:25311244 ↗
PM6 No de novo occurrence of this variant confirmed in a patient with disease and no family history was identified. Details ▾Hide ▴
Still missing
  • No de novo data available.
PP1 No cosegregation data from affected families is available. Details ▾Hide ▴
Still missing
  • No cosegregation data available.
PP4 Insufficient patient phenotype data available to assess whether the variant is observed in a phenotype highly specific for U2AF1-related disease. Details ▾Hide ▴
Still missing
  • No phenotype specificity data.
PP5 No reputable source (expert panel, clinical diagnostic laboratory) has classified this variant as pathogenic for a germline disorder. OncoKB classifies as Likely Oncogenic (somatic context). ClinVar has no expert panel classification. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 4539541 has no classification or submissions extracted.
  • OncoKB: Likely Oncogenic (somatic cancer context
  • not germline).
Still missing
  • No germline expert panel or clinical laboratory classification available.
Sources
clinvar ↗oncokb ↗
BS2 No data available on observation of this variant in healthy adult individuals with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
  • No data on observation in healthy controls with expected full penetrance.
BS4 No cosegregation data showing lack of segregation with disease is available. Details ▾Hide ▴
Still missing
  • No cosegregation data.
BP2 No data available on observation of this variant in trans with a known pathogenic variant or in cis with a pathogenic variant in U2AF1. Details ▾Hide ▴
Still missing
  • No data on co-occurrence with other pathogenic variants.
BP5 No data available on this variant found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No data on alternate molecular basis for disease in a case carrying this variant.
BP6 No reputable source has classified this variant as benign. Details ▾Hide ▴
Still missing
  • No benign classification from any reputable source.
PS5 No data available to assess this criterion. Details ▾Hide ▴
Still missing
  • No evidence available.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable. This is a missense substitution (p.Ser34Phe), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework confirms the variant does not fall into any default null-variant bucket. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a null variant per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_generic_framework ↗
PM3 N/APM3 applies to variants detected in trans with a pathogenic variant in recessive disorders. U2AF1-related disease is not recessively inherited; no biallelic disease association is established. Details ▾Hide ▴
Evidence considered
  • U2AF1 disease mechanism is heterozygous gain-of-function
  • not biallelic recessive.
PM4 N/APM4 applies to protein length changes from in-frame insertions/deletions or stop-loss variants. This is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a protein length change.
BP1 N/ABP1 applies to genes where primarily truncating variants cause disease. U2AF1-related disease is caused by specific missense variants (S34F/Y, Q157P/R) in zinc finger domains, not truncating variants. Details ▾Hide ▴
Evidence considered
  • U2AF1 disease mechanism is missense gain-of-function
  • not loss-of-function through truncation.
BP3 N/ABP3 applies to in-frame insertions/deletions in a repetitive region. This is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Substitution
  • not an in-frame indel.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a missense variant (p.Ser34Phe), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Identifiers

Gene
U2AF1
Transcript
NM_006758.2
Coding (HGVS c.)
NM_006758.2:c.101C>T
Protein (HGVS p.)
NP_006749.1:p.(Ser34Phe)
GRCh38
chr21:43104346 G>A
GRCh37
chr21:44524456 G>A
ClinVar
4539541
COSMIC
COSV52341059

Gene diagram

Every interpreted variant in U2AF1, mapped onto the exon structure of NM_006758.2. Select a row to find it on the plot.

U2AF1NM_006758.2
Fetching transcript structure from UCSC…
gnomAD v4.1 0 / 18,936 alleles AF 0 · 0 homozygotes
gnomAD v2.1 1 / 281,256 alleles AF 3.56e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 18,936 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

gnomAD v2.1

AF 3.6e-06 · 1 / 281,256 alleles · 0 hom
African/African American1 / 24,914 4e-05
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

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).

gnomAD v2.1

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).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.700
BayesDel
0.415

How the predictions were used

PP3 SupportingIn silico predictors support a deleterious effect. REVEL score is 0.7 (above the 0.5 threshold for pathogenic prediction). SpliceAI predicts no splice impact (max delta 0.0), consistent with a missense effect rather than splicing defect. BayesDel score is 0.415 (borderline). Overall, REVEL provides supporting evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.7 (pathogenic-leaning).
  • BayesDel: 0.415 (borderline
  • benign-leaning).
  • SpliceAI: max delta 0.0 (no splice impact predicted).
Still missing
  • HCI Prior not available for U2AF1. BayesDel is borderline.
Sources
revelbayesdelspliceai ↗
BP4 Multiple lines of computational evidence do not suggest a benign impact. REVEL score of 0.7 supports a deleterious effect, and BayesDel score of 0.415 is borderline. SpliceAI predicts no splicing impact (delta 0.0), but REVEL outweighs toward deleterious. BP4 requires consensus evidence of no impact. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.7 (deleterious).
  • BayesDel: 0.415 (borderline).
  • No consensus of benign computational prediction.
Sources
revelbayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a missense variant (p.Ser34Phe), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.7. BayesDel score = 0.415417.

8 paper records listed. 7 cited in the classification.

Cited in the classification

  • Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes.
    U2AF1 S34F was identified as a recurrent missense mutation in 11 of 150 (7.3%) de novo MDS patients, with S34Y in an additional 2 patients. Mutant U2AF1 S34F promoted enhanced splicing and exon skipping in double-reporter and minigene assays in 293T cells, consistent with a gain-of-function mechanism.
    → PS3 → PM1 Names this variant
    PMID 22158538 ↗
    Source detail
    a missense mutation affecting the serine at codon 34 (S34) in U2AF1 was recurrently mutated in 13/150 (8.7%) de novo MDS patients.

    Location Abstract; Results; Figure 3; Online Methods

    Context 293T cells; pTN24 double-reporter splicing assay; GH1 minigene exon skipping assay; FMR1 minigene; MDS patient bone marrow CD34+ cells

  • U2AF1 mutations alter splice site recognition in hematological malignancies.
    Ilagan JO et al. · 2015 Jan
    U2AF1 S34F mutations alter 3′ splice site recognition in hematological malignancies, causing differential splicing of hundreds of genes including DNMT3B, ATR, CASP8, and FANCA. Mutations affecting S34 alter the preferred 3′ splice site motif with a shift from T to C/A at the −3 position.
    → PS3 → PM1 Names this variant
    PMID 25267526 ↗
    Source detail
    U2AF1 mutations are highly specific—they uniformly affect the S34 and Q157 residues within the first and second CCCH zinc fingers of the protein.

    Location Abstract; Results sections "U2AF1 mutations cause allele-specific alterations in the 3′ splice site consensus"; Figures 1-6

    Context K562 erythroleukemic cell lines stably expressing FLAG-tagged U2AF1 (WT, S34F, S34Y, Q157P, Q157R); RNA-seq; minigene splicing reporter assays; in vitro splicing with AdML substrate; TCGA AML transcriptomes

  • U2AF1 mutations alter sequence specificity of pre-mRNA binding and splicing.
    U2AF1 S34F and S34Y mutations alter the sequence specificity of pre-mRNA binding and splicing, shifting preference from T to C at the −3 position of the 3′ splice site. The mutations affect the ZnF1 domain and alter RNA binding, resulting in downstream splicing changes.
    → PS3 → PM1 Names this variant
    PMID 25311244 ↗
    Source detail
    We analyzed splicing changes induced by mutant U2AF1 in primary CD34+ cells from MDS patients and found that U2AF1 S34F and S34Y mutations impart altered sequence-specific RNA binding and splicing.

    Location Abstract; Results; Figures 1-5

    Context Primary human CD34+ hematopoietic cells; RNA-seq; RNA binding assays; minigene splicing reporters

  • Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo.
    Transgenic mice expressing U2AF1 S34F display altered hematopoiesis including leukopenia, monocyte and B-cell reduction, progenitor cell expansion, and altered pre-mRNA splicing in bone marrow progenitor cells by RNA-seq. 633 genes showed differential splicing in mouse common myeloid progenitors expressing U2AF1 S34F. The 3′ splice site sequence preference alteration (T at −3) was conserved across mouse and human.
    → PS3 → PM1 Names this variant
    PMID 25965570 ↗
    Source detail
    Mice expressing mutant U2AF1(S34F) display altered hematopoiesis and changes in pre-mRNA splicing in hematopoietic progenitor cells by whole transcriptome analysis (RNA-seq).

    Location Abstract; Results sections; Figures 1-7; Tables S1-S7

    Context Doxycycline-inducible U2AF1(S34F) transgenic mice; bone marrow transplantation; flow cytometry; RNA-seq of CMP cells; validation in human MDS bone marrow samples and primary CD34+ cells

  • Integrative Profiling of Alternative Splicing Induced by U2AF1 S34F Mutation in Lung Adenocarcinoma Reveals a Mechanistic Link to Mitotic Stress.
    Kim S et al. · 2018 Aug 31
    Functional analysis of U2AF1 S34F missense mutation in lung adenocarcinoma (LUAD) showed induction of alternative splicing changes and a mechanistic link to mitotic stress. Knockdown and overexpression studies revealed splicing alterations affecting mitotic genes.
    → PS3 Names this variant
    PMID 29991672 ↗
    Source detail
    One of the most frequently found is U2AF1 S34F missense mutation.

    Location Title and abstract

    Context Lung adenocarcinoma cell lines; RNA-seq; splicing analysis

  • Spliceosome Mutations Induce R Loop-Associated Sensitivity to ATR Inhibition in Myelodysplastic Syndromes.
    U2AF1 S34F expression causes accumulation of R-loops (RNA:DNA hybrids) and elicits an ATR-dependent checkpoint response. ATR inhibition selectively induces DNA damage and cell death in U2AF1 S34F-expressing cells, including primary human CD34+ hematopoietic progenitors. Splicing alterations occur independently of R-loop formation.
    → PS3 Names this variant
    PMID 30054334 ↗
    Source detail
    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 sections; Figures 1-7

    Context HeLa cells; K562 cells; OCI-AML3 cells; primary human CD34+ hematopoietic progenitor cells; ATR inhibitors (VE-821, VE-822, AZ-20); RNaseH1 overexpression; immunofluorescence (S9.6, γH2AX, p-RPA)

  • The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation.
    Palangat M et al. · 2019 May 1
    U2AF1 S34F, the most common change in the gene, contributes to cancer progression through a noncanonical role in translation regulation, in addition to its known role in splice site selection and alternative splicing.
    → PS3 Names this variant
    PMID 30842218 ↗
    Source detail
    the most common change, S34F, alters a conserved nucleic acid-binding domain, recognition of the 3′ splice site, and alternative splicing of many transcripts

    Location Abstract

    Context Not available from abstract

Other recorded publications

  • American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.
    Cooley LD et al. · 2013
    ACMG technical standards and guidelines for microarray analysis in neoplastic disorders. The variant NM_006758.2:c.101C>T was not identified in this paper.
    Does not name this variant
    PMID 23619274 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 0 / 18,936 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

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).

gnomAD v2.1

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).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 4539541)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.7. BayesDel score = 0.415417.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52341059, n = 340 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.