SF3B1 c.2219G>A, p.Gly740Glu
NM_012433.2:c.2219G>A
COSM133120
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
0.481
Uncertain (Low)
COSMIC Recurrence
36 occurrences
PM1 Criterion Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
SF3B1
Transcript
NM_012433.4
MANE Select
Total Exons
25
Strand
Reverse (−)
Reference Sequence
NC_000002.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_012433.2 | Alternative | 25 exons | Reverse |
| NM_012433.3 | RefSeq Select | 25 exons | Reverse |
Variant Details
HGVS Notation
NM_012433.2:c.2219G>A
Protein Change
G740E
Location
Exon 15
(Exon 15 of 25)
5'
Exon Structure (25 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 740 in gene SF3B1
Alternate Identifiers
COSM133120
Variant interpretation based on transcript NM_012433.4
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
18
Reported mutations in this domain
0
50
100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (18 mutations).
PM1 criterion applied: Located in a mutational hot spot and/or critical and well-established functional domain.
Related Variants in This Domain
No evidence of other pathogenic variants at position 740 in gene SF3B1
Functional Studies
Summary
The SF3B1 G740E variant has been functionally characterized and demonstrates a damaging effect. In vitro studies using HEK293T cells show that this mutation results in a switch-of-function, leading to increased aberrant splicing compared to the wildtype.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.481
0.481
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
sift: D
mutationtaster: D
provean: D
primateai: D
deogen2: D
Benign:
CADD: 5.00
fathmm: T
metasvm: T
metalr: T
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
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 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 variant, not predicted to cause loss-of-function. Therefore, this criterion is not applied at Not Applied strength because the variant is not a null variant.
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: No other variant at codon 740 has been reported as pathogenic. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant at this codon.
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 de novo data reported. Therefore, this criterion is not applied at Not Applied strength because there is no confirmed de novo occurrence.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: In vitro studies in HEK293T cells demonstrate a switch-of-function and increased aberrant splicing compared to wildtype. Therefore, this criterion is applied at Strong strength because the variant has been experimentally shown to be damaging.
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 prevalence data available. Therefore, this criterion is not applied at Not Applied strength because prevalence data are lacking.
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: Codon 740 is not a recognized mutational hotspot in SF3B1 and has no recurrence in COSMIC. Therefore, this criterion is not applied at Not Applied strength because it does not lie in a known hotspot or domain lacking benign variation.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive) in population databases.' The evidence for this variant shows: MAF = 0% in gnomAD and other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from 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: Not applicable for this gene/condition. Therefore, this criterion is not applied at Not Applied strength.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes as a result of in-frame deletions/insertions or stop-loss variants.' The evidence for this variant shows: It is a missense change without alteration of protein length. Therefore, this criterion is not applied at Not Applied strength.
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 changes have been reported at residue 740. Therefore, this criterion is not applied at Not Applied strength.
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 data on de novo status. Therefore, this criterion is not applied at Not Applied strength.
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 segregation data available. Therefore, this criterion is not applied at Not Applied strength.
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 on gene constraint and mechanism. Therefore, this criterion is not applied at Not Applied strength.
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 or gene product.' The evidence for this variant shows: Computational predictions are conflicting, with some tools predicting deleterious and others benign. Therefore, this criterion is not applied at Not Applied strength due to inconsistent in silico evidence.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: No phenotypic or family history data provided. Therefore, this criterion is not applied at Not Applied strength.
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: No external source reports. Therefore, this criterion is not applied at Not Applied strength.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder.' The evidence for this variant shows: Absent in population databases. Therefore, this criterion is not applied at Not Applied strength.
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: Absent in population databases. Therefore, this criterion is not applied at Not Applied strength.
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 observations in healthy individuals. Therefore, this criterion is not applied at Not Applied strength.
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 at Not Applied strength.
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 data available. Therefore, this criterion is not applied at Not Applied strength.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss-of-function causes disease.' The evidence for this variant shows: SF3B1 disease mechanism involves missense variants. Therefore, this criterion is not applied at Not Applied strength.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.' The evidence for this variant shows: No phasing data. Therefore, this criterion is not applied at Not Applied strength.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame insertions/deletions in a repetitive region without known function.' The evidence for this variant shows: It is a missense variant. Therefore, this criterion is not applied at Not Applied strength.
BP4
BP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: Computational predictions are conflicting. Therefore, this criterion is not applied at Not Applied strength due to lack of consistent benign in silico evidence.
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 such case reported. Therefore, this criterion is not applied at Not Applied strength.
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 source. Therefore, this criterion is not applied at Not Applied strength.
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 variant. Therefore, this criterion is not applied at Not Applied strength.