About SRSF2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SRSF2 c.283C>A, p.(Pro95Thr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 2
Benign evidence criteria: 1
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate
Pro95 is located within the RNA recognition motif (RRM) domain of SRSF2, a well-established functional domain critical for RNA binding and splicing. This codon is a known mutational hotspot in hematologic malignancies, with recurrent pathogenic missense changes (P95H, P95L, P95R) documented in COSMIC. Cancer Hotspots analysis confirms the residue is statistically significant.
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in population databases: gnomAD v2.1 exomes AF=8.35e-06 (2/239,628 alleles, 0 homozygotes) and gnomAD v4.1 AF=6.83e-06 (11/1,611,376 alleles, 0 homozygotes). Both are well below the 0.1% threshold for PM2. Absent from gnomAD-Canada.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no significant impact on the gene product: REVEL score 0.444 (below pathogenic threshold), BayesDel score -0.15213 (predicts benign), and SpliceAI predicts no splicing alteration (max delta score 0.00).
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting, BP4 supporting; combination = 1 moderate + 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.
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
11 / 1,611,376 alleles
gnomAD v4.1: 11 / 1,611,376 alleles. Recorded AF 6.82646e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.34627e-06; MAF= 0.00083%, 2/239628 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.87716e-05; MAF= 0.00188%, 2/106544 alleles, homozygotes = 0); grpmax FAF= 3.12e-06.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
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 Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
11 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57970203, n = 11 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 3 met · 14 not met · 2 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM1 (moderate): Pro95 is located within the RRM domain of SRSF2, a well-established functional domain and mutational hotspot where other pathogenic missense changes (P95H, P95L, P95R) have been documented in COSMIC. Cancer Hotspots confirms the residue as statistically significant.
PM2 (supporting): This variant is present at extremely low frequency in gnomAD (v2.1: 2/239,628 alleles, AF=8.35e-06; v4.1: 11/1,611,376 alleles, AF=6.83e-06), well below the 0.1% PM2 threshold. No homozygotes observed. Absent from gnomAD-Canada.
BP4 (supporting): Multiple lines of computational evidence suggest no significant impact: REVEL score 0.444, BayesDel score -0.15213 (benign), and SpliceAI max delta score 0.00 (no predicted splicing effect).
Overall assessment: 1 moderate pathogenic criterion (PM1) + 1 supporting pathogenic criterion (PM2) + 1 supporting benign criterion (BP4). Using generic ACMG/AMP 2015 combination rules (PMID:25741868), this combination of criteria is insufficient to reach Likely Pathogenic (requires ≥2 moderate or 1 moderate + ≥4 supporting), Likely Benign (requires ≥1 strong benign + 1 supporting benign, or ≥2 supporting benign), or Benign. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 3
PM1 ModeratePro95 is located within the RNA recognition motif (RRM) domain of SRSF2, a well-established functional domain critical for RNA binding and splicing. This codon is a known mutational hotspot in hematologic malignancies, with recurrent pathogenic missense changes (P95H, P95L, P95R) documented in COSMIC. Cancer Hotspots analysis confirms the residue is statistically significant. Details ▾Hide ▴
Evidence considered
- Pro95 in RRM domain
- statistically significant cancer hotspot
- recurrent somatic mutations at same residue (P95H/L/R in COSMIC
- n=11 for this variant in COSMIC)
Sources
PM2 SupportingThis variant is present at extremely low frequency in population databases: gnomAD v2.1 exomes AF=8.35e-06 (2/239,628 alleles, 0 homozygotes) and gnomAD v4.1 AF=6.83e-06 (11/1,611,376 alleles, 0 homozygotes). Both are well below the 0.1% threshold for PM2. Absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 2/239
- 628 alleles (AF=0.00083%)
- gnomAD v4.1: 11/1
- 611
- 376 alleles (AF=0.00068%)
- gnomAD-Canada: absent
- no homozygotes
Sources
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product: REVEL score 0.444 (below pathogenic threshold), BayesDel score -0.15213 (predicts benign), and SpliceAI predicts no splicing alteration (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL=0.444
- BayesDel=-0.15213
- SpliceAI max delta=0.00
- all concordantly suggest no damaging effect
Sources
Not met · 14 · evaluated, threshold not reached
PS2 No reports of de novo occurrence of SRSF2 p.Pro95Thr in a patient with a matching phenotype and confirmed parentage were identified in the literature or databases. Details ▾Hide ▴
Evidence considered
- Exploratory search for de novo reports returned no results
Still missing
- No family-based de novo sequencing studies available for this variant
PS3 No well-established in vitro or in vivo functional studies specifically assessing the functional impact of p.Pro95Thr were identified. Published functional studies of SRSF2 codon 95 variants focus on the more common P95H, P95L, and P95R substitutions (PMID:25687329, PMC7410493) and do not include data on P95T. Details ▾Hide ▴
Evidence considered
- Functional studies on P95H/L/R exist but none include P95T
- no variant-specific functional data available
Still missing
- No functional assay data specific to p.Pro95Thr
Sources
25687329
PS4 No case-control studies demonstrating statistically significant enrichment of p.Pro95Thr in affected individuals versus controls were identified. The variant is extremely rare in gnomAD but no affected cohort frequency data are available for comparison. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=8.35e-06 (2/239
- 628)
- gnomAD v4.1 AF=6.83e-06 (11/1
- 611
- 376)
- no affected cohort enrichment data
Still missing
- No case-control or cohort enrichment studies for this variant
Sources
PM5 While other missense changes at Pro95 (P95H, P95L, P95R) are well-established somatic driver mutations in hematologic malignancies, no germline pathogenic or likely pathogenic classification exists in ClinVar for a different missense substitution at this residue. PM5 requires a different missense change at the same residue with an established pathogenic classification, which is not met in the germline context. Details ▾Hide ▴
Evidence considered
- P95H/L/R are recurrent somatic cancer mutations in COSMIC but lack germline ClinVar pathogenic classification
- PM5 candidate harvesting returned no eligible comparators
Still missing
- No ClinVar pathogenic/likely pathogenic germline classification for a different missense at Pro95
Sources
pm5_candidates
PM6 No reports of presumed de novo occurrence (without confirmation of parentage) were identified for this variant. Details ▾Hide ▴
Evidence considered
- Exploratory search for de novo reports returned no results
Still missing
- No de novo observations in the literature
PP1 No family segregation data are available for this variant. SRSF2 germline mutations are not commonly associated with inherited syndromes for which segregation studies have been performed. Details ▾Hide ▴
Evidence considered
- No cosegregation data identified
Still missing
- No family studies or segregation data for this variant
PP3 Multiple in silico predictors do not support a damaging effect: REVEL score 0.444 (below the typical pathogenic threshold of 0.5), BayesDel score -0.152 (negative score indicates benign), and SpliceAI predicts no splicing impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL=0.444
- BayesDel=-0.15213
- SpliceAI max delta=0.00
- HCI prior: gene not supported
Sources
PP5 This variant is absent from ClinVar. No reputable source (clinical laboratory, expert panel) has reported this variant as pathogenic. Details ▾Hide ▴
BA1 The allele frequency in gnomAD is far below the 1% BA1 threshold: v2.1 AF=0.00083%, v4.1 AF=0.00068%. Details ▾Hide ▴
BS1 The allele frequency in gnomAD is below the 0.3% BS1 threshold: v2.1 AF=0.00083%, v4.1 AF=0.00068%. Details ▾Hide ▴
BS3 No well-established in vitro or in vivo functional studies demonstrate that p.Pro95Thr has no damaging effect on protein function or splicing. Published functional studies on Pro95 mutations (P95H, P95L, P95R) show altered function, but p.Pro95Thr has not been specifically tested. Details ▾Hide ▴
Evidence considered
- No functional studies demonstrating normal/benign function for P95T
- existing Pro95 studies (P95H/L/R) show damaging effects
Still missing
- No functional data for P95T
BS4 No family studies are available to assess lack of segregation of this variant with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No segregation data identified
Still missing
- No family segregation studies available
BP5 No evidence is available that this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No data on alternate molecular diagnoses in carriers of this variant
Still missing
- No case reports with alternate molecular findings
BP6 This variant is absent from ClinVar. No reputable source has reported this variant as benign without the evidence being available for independent evaluation. Details ▾Hide ▴
Not assessed · 2 · no assessment recorded
PP2 Insufficient data to determine whether SRSF2 has a low rate of benign missense variation (e.g., high missense Z-score from gnomAD constraint metrics). PP2 cannot be applied without gene-level missense constraint metrics. Details ▾Hide ▴
Still missing
- gnomAD missense constraint data (Z-score) not available in evidence packet
- exploratory suggested verification but data not retrieved
PP4 No specific patient phenotype or clinical information was provided with this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology, which cannot be evaluated without clinical context. Details ▾Hide ▴
Still missing
- No patient phenotype provided
- cannot assess phenotype specificity
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_003016.4:c.283C>A is a missense variant (p.Pro95Thr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). Generic PVS1 framework per ClinGen SVI recommendations (PMC6185798) does not apply to missense changes. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 95
- variant bucket 'other'
- apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo other nucleotide change producing the same amino acid substitution (p.Pro95Thr) has been reported as pathogenic. The known pathogenic changes at codon 95 (c.284C>A/p.Pro95His; c.284C>T/p.Pro95Leu; c.284C>G/p.Pro95Arg) produce different amino acid substitutions. Details ▾Hide ▴
Evidence considered
- Common pathogenic changes at Pro95 are P95H
- P95L
- P95R — all different amino acids than Threonine
BS2 N/ASRSF2 is not associated with a well-established Mendelian disorder with full penetrance at an early age. BS2 requires observation in a healthy adult individual for a disorder where full penetrance is expected early in life. Without a clearly defined SRSF2 germline disease with known penetrance, BS2 cannot be properly applied. Details ▾Hide ▴
Evidence considered
- SRSF2 germline disease context is literature-only
- with no established Mendelian syndrome or clear early-onset full-penetrance disorder
Sources
pvs1_gene_context
BP1 N/ASRSF2-related disease is driven primarily by missense variants, not truncating variants. BP1 applies when a gene's disease mechanism is primarily through truncating variants and the variant in question is missense. Details ▾Hide ▴
Evidence considered
- SRSF2 pathogenic variants are predominantly missense (P95H/L/R)
- not a gene where truncating variants are the primary disease mechanism
Sources
pvs1_gene_context
BP2 N/ASRSF2 is not established as a Mendelian disease gene with clearly defined dominant or recessive inheritance. BP2 requires observation in trans with a pathogenic variant in a gene with established recessive inheritance, or in cis with a pathogenic variant in a dominant disorder. Neither context is applicable here. Details ▾Hide ▴
Evidence considered
- SRSF2 germline disease not established as Mendelian
- recessive inheritance not supported
Sources
pvs1_gene_context
BP7 N/ANM_003016.4:c.283C>A is a missense variant (p.Pro95Thr), not a synonymous or intronic variant. BP7 applies only to synonymous variants predicted not to affect splicing. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is for synonymous variants
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion (Richards et al., PMID:25741868). In the generic ACMG/AMP framework, this concept is subsumed by PM5 (novel missense at residue with known pathogenic missense). Assessed under PM5 instead. Details ▾Hide ▴
Evidence considered
- PS5 not present in ACMG/AMP 2015 criteria set
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- SRSF2
- Transcript
- NM_003016.4
- Coding (HGVS c.)
- NM_003016.4:c.283C>A
- Protein (HGVS p.)
- NP_003007.2:p.(Pro95Thr)
- GRCh38
- chr17:76736878 G>T
- GRCh37
- chr17:74732960 G>T
- COSMIC
- COSV57970203
Gene diagram
Every interpreted variant in SRSF2, mapped onto the exon structure of NM_003016.4. Select a row to find it on the plot.
SRSF2NM_003016.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in SRSF2
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
11 / 1,611,376 alleles
AF 6.83e-06 · 0 homozygotes · FAF 4.29e-06
gnomAD v2.1
2 / 239,628 alleles
AF 8.35e-06 · 0 homozygotes · FAF 3.12e-06
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 6.8e-06 · 11 / 1,611,376 alleles · 0 hom · FAF 4.3e-06
| South Asian1 / 91,010 | 1.1e-05 |
| European (non-Finnish)10 / 1,179,354 | 8.5e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 8.3e-06 · 2 / 239,628 alleles · 0 hom · FAF 3.1e-06
| European (non-Finnish)2 / 106,544 | 1.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.82646e-06; MAF= 0.00068%, 11/1611376 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09878e-05; MAF= 0.00110%, 1/91010 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.34627e-06; MAF= 0.00083%, 2/239628 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.87716e-05; MAF= 0.00188%, 2/106544 alleles, homozygotes = 0); grpmax FAF= 3.12e-06.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.444
- BayesDel
- -0.152
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product: REVEL score 0.444 (below pathogenic threshold), BayesDel score -0.15213 (predicts benign), and SpliceAI predicts no splicing alteration (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL=0.444
- BayesDel=-0.15213
- SpliceAI max delta=0.00
- all concordantly suggest no damaging effect
Sources
PP3 Multiple in silico predictors do not support a damaging effect: REVEL score 0.444 (below the typical pathogenic threshold of 0.5), BayesDel score -0.152 (negative score indicates benign), and SpliceAI predicts no splicing impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL=0.444
- BayesDel=-0.15213
- SpliceAI max delta=0.00
- HCI prior: gene not supported
Sources
BP7 N/ANM_003016.4:c.283C>A is a missense variant (p.Pro95Thr), not a synonymous or intronic variant. BP7 applies only to synonymous variants predicted not to affect splicing. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is for synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.444. BayesDel score = -0.15213.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
11 / 1,611,376 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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_003016.4%3Ac.283C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-74732960-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-76736878-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003016.4%3Ac.283C…
- OncoKB ↗www.oncokb.org/gene/SRSF2/P95T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=146200521
- Cancer hotspots ↗www.cancerhotspots.org/
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= 6.82646e-06; MAF= 0.00068%, 11/1611376 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09878e-05; MAF= 0.00110%, 1/91010 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.34627e-06; MAF= 0.00083%, 2/239628 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.87716e-05; MAF= 0.00188%, 2/106544 alleles, homozygotes = 0); grpmax FAF= 3.12e-06.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.444. BayesDel score = -0.15213.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-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; COSV57970203, n = 11 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.