The SRSF2 NM_003016.4:c.284C>A (NP_003007.2:p.(Pro95His)) missense variant has previously been reported in somatic cancers (COSMIC; COSV57969816, n = 500 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: P95H caused 548 misregulated splicing events in CRISPR knock-in cells and concordant RNA-binding, cellular, and in vivo hematopoietic abnormalities across four studies. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
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.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.SRSF2 encodes a spliceosome protein that helps process pre-mRNA into mature messenger RNA and also supports mRNA transport and use by cells. Changes affecting SRSF2 are associated with myelodysplastic syndromes, acute myeloid leukemia, and other myeloid disorders; in these cancers, abnormal RNA splicing can disrupt blood-cell development, cell growth, and survival.
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: P95H caused 548 misregulated splicing events in CRISPR knock-in cells and concordant RNA-binding, cellular, and in vivo hematopoietic abnormalities across four studies.
Met at supporting strength: gnomAD v4.1 grpmax FAF is 0.00009783, just below the 0.0001 PM2 threshold, with zero homozygotes.
Met, supporting: the exact variant occurred with homozygous JAK2 V617F and ASXL1 c.1720-2A>G, providing an alternate molecular basis for the reported disease progression.
VUS: PS3 (strong), PM2 (supporting), and BP5 (supporting) do not satisfy a generic ACMG/AMP pathogenic or benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 157 / 1,610,816 alleles. Recorded AF 9.74661e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000103396; MAF= 0.01034%, 28/270804 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000172332; MAF= 0.01723%, 21/121858 alleles, homozygotes = 0); grpmax FAF= 0.00013143.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.419. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Pathogenic. ClinVar API review status: criteria provided, single submitter.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV57969816, n = 500 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 · 7 not met · 14 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No criterion in this group is assigned because the available evidence does not fully satisfy the governing requirements for an independent same-amino-acid pathogenic comparator, a benign-variation-free PM1 hotspot/domain, a pathogenic alternate same-residue comparator, or the gene-level PP2/BP1 mechanisms.
Variant-specific, biologically relevant cellular, biochemical, and in vivo studies support PS3 and provide no support for BS3.
The exact variant is observed in myeloid-neoplasm cases, including 31 cases in PMID:21909114, but the available literature does not establish the PS4 case-control OR/RR and confidence interval requirement.
PP4 cannot be assessed because a sufficiently specific patient phenotype or family history is not available.
PP5 and BP6 are not met because ClinVar provides only a single-submitter laboratory assertion and no expert-panel classification.
BP5 is supported by a case report describing the exact variant alongside homozygous JAK2 V617F and ASXL1 c.1720-2A>G, although its source-registry registration requires human review.
Both criteria are applicable to this missense variant through the REVEL path only; the REVEL score is below PP3 supporting and above BP4 supporting thresholds.
SpliceAI is not used for a missense variant, and BayesDel is not available for generic ACMG-strength assignment.
No criteria match.
PS3 is met at strong strength. Multiple independent, variant-specific functional studies evaluated SRSF2 p.Pro95His (P95H), corresponding to NM_003016.4:c.284C>A, using orthogonal systems and wild-type comparators. CRISPR knock-in heterozygous K562 cells showed 548 misregulated splicing events and sequence-dependent changes in RNA-binding affinity (PMID:26261309). Conditional endogenous P95H mouse models demonstrated hematopoietic dysplasia, impaired differentiation, altered transcriptome/splicing, and changed RNA-binding specificity (PMID:25965569); additional mouse and human-cell studies independently showed altered splicing and hematopoietic effects (PMID:26124281, PMID:27135740, PMID:31040863). The evidence is biologically relevant, concordant, and reproducible across cellular, biochemical, and in vivo models, although it is not described as a validated clinical diagnostic-laboratory assay.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PM2 is met at supporting strength using the current all-comers gnomAD v4.1 dataset. The filtering grpmax FAF is 0.00009783, which is below the supplied generic PM2 threshold of 0.0001, with 157/1,610,816 alleles and no homozygotes. gnomAD v2.1 also shows an extremely low frequency but its grpmax FAF is 0.00013143, slightly above the threshold; therefore the conclusion depends on the larger, more current v4.1 dataset rather than an assertion that the variant is absent. The available non-cancer v2.1 exome subset has grpmax FAF 0.00012656 and does not meet the supplied cutoff, but no governing VCEP rule requires that subset here.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
A case report explicitly identifies the exact SRSF2 c.284C>A (p.Pro95His) variant in a patient with polycythemia vera progressing to secondary myelofibrosis who also carried homozygous JAK2 V617F and an ASXL1 splice-site variant. The abstract states that the rapid progression was probably due to coexistence of these alterations and that ASXL1 cooperated with JAK2 V617F, providing an alternate molecular basis for the disease course. This supports BP5 at supporting strength. The source was retrieved in the case's PVS1 article material but is not present as a key in source_registry.json, so a human should verify and register the citation before relying on this assertion operationally.
Variant found in a case with an alternate molecular basis for disease.
The variant is a missense substitution, so the generic rule selects the REVEL path only; splice prediction is not used for this situation. REVEL is 0.419, below the generic PP3 supporting threshold of >= 0.644 calibrated by ClinGen SVI (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established, and no other applicable calibrated computational evidence meets PP3.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The exact variant has a ClinVar Pathogenic submission from one clinical laboratory with a single-submitter review status, not an expert-panel classification. Under the required generic PP5 rule, ordinary laboratory submissions and non-expert assertions do not trigger PP5, so the ClinVar Pathogenic label cannot establish this criterion.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The applicable filtering frequency is the gnomAD v4.1 grpmax FAF of 0.00009783, based on 157/1,610,816 total alleles; this is far below the generic BA1 threshold of 0.05 (5%). The gnomAD v2.1 grpmax FAF is also only 0.00013143. The higher Ashkenazi Jewish gnomAD v4.1 point estimate (0.000169308 from 5/29,532 alleles) is not used for BA1 because the required filtering FAF, not the popmax point estimate, is the relevant metric.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met on the available population data. The gnomAD v4.1 filtering grpmax FAF is 0.00009783 and the gnomAD v2.1 filtering grpmax FAF is 0.00013143, both well below the supplied generic default threshold of 0.01. The frequency is not elevated in a qualifying population; the highest gnomAD v4.1 population point estimate is only 0.000169308 in Ashkenazi Jewish individuals and is not substituted for FAF. No disease prevalence, penetrance, or allelic-heterogeneity calculation indicates that a lower frequency should be interpreted as greater than expected for the disorder.
Allele frequency is greater than expected for the disorder.
BS3 is not met. The reviewed variant-specific studies do not show absence of damaging effect on SRSF2 function or splicing; instead, they report altered RNA-binding specificity, hundreds of abnormal splicing events, altered exon selection, and hematopoietic abnormalities in cellular and in vivo models. No well-established benign functional or splicing result for P95H was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense substitution, so the generic rule selects the REVEL path only; SpliceAI cannot substitute for REVEL and is not used for this situation. REVEL is 0.419, above the generic BP4 supporting threshold of <= 0.29 calibrated by ClinGen SVI (Pejaver et al. 2022, PMID:36413997), so it does not support no impact. BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
No exact-variant ClinVar expert-panel classification of Benign or Likely benign is present. ClinVar contains a Pathogenic single-submitter laboratory assertion and no expert-panel submission, which cannot trigger BP6 and does not provide the required benign reputable-source assertion under the instructed rule.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is SRSF2 p.Pro95His, but the available evidence does not identify a previously established pathogenic variant producing the same amino-acid change through a different nucleotide change. The ClinVar record is for this same nucleotide change and has single-submitter Pathogenic status, so it does not establish the required independent PS1 comparator.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
The available evidence identifies SRSF2 c.284C>A (p.Pro95His) in functional and somatic myeloid-neoplasm studies but provides no proband-level evidence establishing a germline de novo occurrence, no confirmed maternity and paternity, and no documented absence of family history. Therefore the ACMG/AMP PS2 definition cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The literature contains affected-case observations but does not provide the required case-control comparison for the exact variant. PMID:21909114 reports SRSF2 P95H in 31 cases within a 582-specimen myeloid-neoplasm cohort, but it does not report unaffected or population controls for P95H, an odds ratio, or a confidence interval. The governing ACMG/AMP note requires an OR or RR >5.0 with a confidence interval excluding 1.0; because no valid matched-ancestry case-control estimate and CI are available, the threshold cannot be evaluated. The gnomAD v4.1 frequency is 157/1,610,816 alleles (AF 0.0000974661), but the affected cohort's case frequency cannot be paired with a matched-ancestry control frequency to produce a reliable estimate here. The literature_pass PS4 leads PMID:20963938 and PMID:23970018 were checked as leads; the case packet supplies neither an abstract nor full text establishing exact-variant case-control counts for either source.
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.
P95 is reported as a recurrent SRSF2 hotspot: PMID:21909114 reports 31 P95H cases among 56 SRSF2 mutations and places P95 between the RNA recognition motif and arginine/serine-rich domains; the Cancer Hotspots result also states that the variant lies in a statistically significant hotspot. However, the available evidence does not establish that the hotspot or surrounding region is free of benign variation, which is required by the generic PM1 definition.
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 case evidence does not establish a recessive SRSF2 disorder, a pathogenic allele in the same affected proband, or phase showing NM_003016.4:c.284C>A in trans. No parent or offspring testing, compound-heterozygous observation, or affected-proband trans observation is documented. The available SRSF2 literature describes heterozygous somatic cancer models and does not provide qualifying germline PM3 evidence for this variant.
For recessive disorders, detected in trans with a pathogenic variant...Note: This requires testing of parents (or offspring) to determine phase.
The evidence documents other SRSF2 substitutions at residue 95, including P95L and P95R, but does not establish either alternate missense change as pathogenic under the governing generic rule. Therefore, the required pathogenic same-residue comparator for PM5 is not confirmed.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
The available evidence identifies SRSF2 c.284C>A (p.Pro95His) in functional and somatic myeloid-neoplasm studies but provides no proband-level evidence establishing an assumed de novo occurrence, and no parental testing or family-history information is reported. Therefore the ACMG/AMP PM6 definition cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No affected relatives, pedigree, genotype results in family members, phenotype concordance, or meioses are documented for SRSF2 c.284C>A (p.Pro95His). The available variant-specific literature is functional or somatic and does not provide co-segregation evidence, so PP1 cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The available evidence shows recurrent somatic SRSF2 missense mutations and functional effects at P95, but it does not establish both required gene-level conditions for PP2: a low rate of benign missense variation and missense variants as a common disease mechanism in the applicable disease context.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The available evidence does not provide a patient phenotype or family history sufficiently specific for a disease with a single genetic etiology. The case materials describe a somatic myeloid-neoplasm context and recurrent SRSF2 P95H biology, but no exact patient's diagnostic phenotype or phenotype-specific differential is supplied for applying PP4.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available evidence. gnomAD reports no homozygotes, but the BS2 rule requires an observed healthy adult individual in the relevant inheritance model and assumes full penetrance with early-age disease; the case does not establish a governing germline disease, inheritance pattern, expected age of onset, or penetrance for SRSF2 p.Pro95His. Heterozygous presence in a population database alone is therefore insufficient to apply BS2.
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 with documented absence of the variant are reported for SRSF2 c.284C>A (p.Pro95His). The available variant-specific literature does not provide a family pedigree or non-segregation results, so lack of segregation cannot be evaluated and BS4 cannot be assessed.
Lack of segregation in affected members of a family.
The available evidence does not show that SRSF2-associated disease is caused primarily by truncating variants. The literature instead documents recurrent somatic missense mutations at Pro95, but that observation does not establish the converse BP1 gene-level pattern.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed because the available case evidence does not document NM_003016.4:c.284C>A in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern. No affected-proband allele pair, phase result, or parent/offspring testing establishes either configuration.
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.
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_003016.4:c.284C>A in SRSF2 is a missense substitution predicted to produce NP_003007.2:p.(Pro95His). 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 SRSF2, 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_003016.4:c.284C>A in SRSF2 is a missense substitution predicted to produce NP_003007.2:p.(Pro95His). 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 SRSF2, 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_003016.4:c.284C>A in SRSF2 is a missense substitution predicted to produce NP_003007.2:p.(Pro95His). 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 SRSF2, 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_003016.4:c.284C>A in SRSF2 is a missense substitution predicted to produce NP_003007.2:p.(Pro95His). 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 SRSF2, 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 SRSF2, mapped onto the exon structure of NM_003016.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Ashkenazi Jewish5 / 29,532 | 0.00017 |
| European (non-Finnish)134 / 1,178,968 | 0.00011 |
| Remaining individuals5 / 62,344 | 8e-05 |
| European (Finnish)4 / 62,376 | 6.4e-05 |
| Admixed American3 / 59,920 | 5e-05 |
| African/African American3 / 74,864 | 4e-05 |
| South Asian3 / 90,988 | 3.3e-05 |
| European (non-Finnish)21 / 121,858 | 0.00017 |
| Remaining individuals1 / 6,960 | 0.00014 |
| Ashkenazi Jewish1 / 10,070 | 9.9e-05 |
| South Asian2 / 30,446 | 6.6e-05 |
| East Asian1 / 19,166 | 5.2e-05 |
| African/African American1 / 22,836 | 4.4e-05 |
| Admixed American1 / 35,080 | 2.9e-05 |
This variant is present in gnomAD v4.1 (AF= 9.74661e-05; MAF= 0.00975%, 157/1610816 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000169308; MAF= 0.01693%, 5/29532 alleles, homozygotes = 0); grpmax FAF= 9.783e-05.
This variant is present in gnomAD v2.1 (AF= 0.000103396; MAF= 0.01034%, 28/270804 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000172332; MAF= 0.01723%, 21/121858 alleles, homozygotes = 0); grpmax FAF= 0.00013143.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, so the generic rule selects the REVEL path only; splice prediction is not used for this situation. REVEL is 0.419, below the generic PP3 supporting threshold of >= 0.644 calibrated by ClinGen SVI (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established, and no other applicable calibrated computational evidence meets PP3.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is a missense substitution, so the generic rule selects the REVEL path only; SpliceAI cannot substitute for REVEL and is not used for this situation. REVEL is 0.419, above the generic BP4 supporting threshold of <= 0.29 calibrated by ClinGen SVI (Pejaver et al. 2022, PMID:36413997), so it does not support no impact. BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
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_003016.4:c.284C>A in SRSF2 is a missense substitution predicted to produce NP_003007.2:p.(Pro95His). 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 SRSF2, 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
REVEL score = 0.419. BayesDel score = -0.151583.
9 paper records listed. 5 cited in the classification.
Here we studied the biological and transcriptional effects of somatic expression of the common SRSF2P95H mutation in the hematopoietic compartment.
Location Introduction, final paragraph; Results sections titled ‘Srsf2P95H Mutant Mice Develop MDS...’ and ‘SRSF2 Proline 95 Mutations Alter RNA Binding Specificity...’ (pp. 618–625)
Context Conditional endogenous Srsf2P95H knock-in mice with hematopoietic transplantation and phenotyping; RNA-seq; K562 expression; ITC and NMR binding assays; EZH2 isoform-specific RT-PCR and nonsense-mediated-decay assays.
the P95H missense mutation and P95 to R102 in-frame 8-amino-acid deletion caused significant changes in alternative splicing.
Location Abstract; Results, ‘SRSF2 Mutants altered a large RNA splicing program,’ paragraphs beginning at lines 323 and 344; Discussion, paragraphs beginning at lines 451 and 455
Context Human MDS-L cells with doxycycline-inducible endogenous SRSF2 shRNA and shRNA-resistant wild-type or P95H rescue; RASL-seq profiling of 5,530 alternatively spliced mRNA isoforms; murine bone-marrow overexpression experiments.
We found that SRSF2 (P95H) misregulates 548 splicing events (<1% of total).
Location Abstract; Results, "Mutant SRSF2 Misregulates Hundreds of Splicing Events"; Fig. 3 and Fig. 6
Context CRISPR/Cas9 knock-in of heterozygous SRSF2 P95H into K562 leukemia cells; RNA-seq and RT-PCR splicing analysis; transient expression in 293T cells; RNA gel-shift and coimmunoprecipitation assays.
We engineered mice that express hemizygous Srsf2P95H mutant alleles in an inducible manner.
Location Results, first experimental paragraph; Fig. 1 and Supplementary Fig. 1
Context Inducible conditional Srsf2P95H mouse hematopoietic models, bone-marrow transplantation, RNA-seq and differential-splicing analysis, leukemia models, and human hematopoietic cell experiments.
In this study, we characterized MDS-associated SRSF2 mutants (P95H, P95L, and P95R).
Location Abstract
Context HeLa-cell localization; in-vitro IgM pre-mRNA splicing and RNA co-immunoprecipitation; stable K562-cell expression followed by RNA sequencing, motif analysis, and EZH2 RT-PCR validation.
SRSF2 mutations exclusively occurred at P95 within an intervening sequence between the RNA recognition motif (RRM) and arginine/serine-rich (RS) domains (Fig. 2 and Supplementary Figs 8 and 9).
Results, "Frequent mutations in splicing machinery"; Figure 2
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= 9.74661e-05; MAF= 0.00975%, 157/1610816 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000169308; MAF= 0.01693%, 5/29532 alleles, homozygotes = 0); grpmax FAF= 9.783e-05.
This variant is present in gnomAD v2.1 (AF= 0.000103396; MAF= 0.01034%, 28/270804 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000172332; MAF= 0.01723%, 21/121858 alleles, homozygotes = 0); grpmax FAF= 0.00013143.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 3765039)
REVEL score = 0.419. BayesDel score = -0.151583.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57969816, n = 500 times).
This variant lies in a statistically significant hotspot.