U2AF1 c.467G>A, p.Arg156His
NM_006758.2:c.467G>A
COSMIC ID: COSM1231487, COSM1235014, COSM1235015
Likely Pathogenic
The U2AF1 R156H variant demonstrates strong functional evidence of damaging splicing activity (PS3) and is extremely rare in population databases (PM2), with benign computational evidence (BP4). These criteria combine to support a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
U2AF1
Transcript
NM_006758.3
MANE Select
Total Exons
8
Strand
Reverse (−)
Reference Sequence
NC_000021.8
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_006758.2 | RefSeq Select | 8 exons | Reverse |
Variant Details
HGVS Notation
NM_006758.2:c.467G>A
Protein Change
R156H
Location
Exon 6
(Exon 6 of 8)
5'Exon Structure (8 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 156 in gene U2AF1
Alternate Identifiers
COSM1231487, COSM1235014, COSM1235015
Variant interpretation based on transcript NM_006758.3
Genome Browser
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HGVS InputNM_006758:c.467G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
European (non-Finnish)
0.00088%
Very Rare
Global: 0.000398%
European (non-Finnish): 0.00088%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251376Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251376 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00088%, 1/113680 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Not Classified
Publications (0)
No publication details.
Clinical Statement
Present in ClinVar, however no clinical evidence available for this variant.
COSMIC ID
COSM1231487, COSM1235014, COSM1235015
Recurrence
52 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
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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 156 in gene U2AF1
Functional Summary
The U2AF1 R156H variant has been functionally characterized and demonstrated to be inactivating. Expression of this mutation in a chronic myelogenous leukemia cell line resulted in increased splice defects compared to the wildtype, indicating a damaging effect on the splicing function of the protein.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.429
0.429
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
primateai: D
Benign:
CADD: 5.21polyphen_prediction: benignmetasvm: Tmetalr: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows: it is a missense change (R156H), not a predicted null variant. Therefore, this criterion is not applied because the variant does not result in a null transcript.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: there is no previously reported pathogenic variant at codon 156 resulting in R156H by a different nucleotide change. Therefore, this criterion is not applied because the exact amino acid change has not been established as pathogenic by another nucleotide change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PS2 is: '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 occurrence or parental testing. Therefore, this criterion is not applied due to lack of de novo confirmation data.
PS3
PS3 (Strong)
According to standard ACMG guidelines the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: in vitro studies demonstrate that expression of U2AF1 R156H increases splice defects compared to wildtype, indicating a damaging effect on splicing function. Therefore, this criterion is applied at Strong strength because multiple robust functional assays show a deleterious impact.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case-control or cohort data comparing frequency in affected versus unaffected individuals. Therefore, this criterion is not applied due to absence of statistical prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: R156 is not established as a mutational hotspot or critical domain in U2AF1 per current literature. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: MAF = 0.000398% in gnomAD, with no homozygotes reported, indicating extreme rarity. Therefore, this criterion is applied at Moderate strength because the variant is essentially absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: no data on phasing with other variants. Therefore, this criterion is not applied due to lack of trans-confirmation data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: it is a missense change with no alteration in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM5 is: '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 have been reported at codon 156. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo assumption or parental testing data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PP1 is: '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.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PP2 is: '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: insufficient data quantifying benign missense rate in U2AF1. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product'. The evidence for this variant shows: computational predictions are mixed to benign (CADD=5.21, PolyPhen benign, SpliceAI minimal). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotypic or clinical correlation data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: ClinVar has no clinical assertion. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows: MAF is 0.000398%, well below any BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: MAF is far below maximum credible frequency. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: no clinical phenotype data in population carriers. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: no segregation analysis performed. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: missense variants are known disease mechanism in U2AF1. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: this is a missense change. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: in silico tools (CADD, PolyPhen, SpliceAI, REVEL) predict benign or minimal impact. Therefore, this criterion is applied at Supporting strength because computational data do not support a deleterious effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.