About ZRSR2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ZRSR2 c.398_399del, p.(Glu133GlyfsTer11)
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.
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
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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: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_005089.3:c.398_399del is a frameshift variant in exon 5 of 11, predicted to cause premature termination at codon 143 (p.Glu133GlyfsTer11), removing 340 of 483 amino acids including the zinc finger and RS-rich domains. NMD is predicted as the premature termination codon occurs more than 55 nucleotides upstream of the last exon-exon junction. ZRSR2 loss-of-function is an established germline disease mechanism supported by literature describing germline ZRSR2 mutations in oral-facial-digital syndrome and aplastic anemia. Under the ClinGen SVI PVS1 decision framework (PMC6185798), frameshift variants meeting the gene-level LOF gate are classified as PVS1 at very_strong strength.
PM2Moderate
PM2 · moderate
NM_005089.3:c.398_399del is absent from all population databases queried, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). For a rare disease-associated gene on the X chromosome, complete absence from large population cohorts (<0.1% under non-VCEP generic ACMG) supports a pathogenic interpretation.
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: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
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 Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57067023, n = 1 times).
Cancer Hotspots
This variant does not lie 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.
29 criteria with recorded statuses: 2 met · 19 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005089.3:c.398_399del is a frameshift variant in exon 5 of ZRSR2 predicted to cause premature termination at codon 143 (p.Glu133GlyfsTer11), resulting in loss of approximately 70% of the protein including functionally critical zinc finger and RS-rich domains.
ZRSR2 loss-of-function is an established germline disease mechanism: germline ZRSR2 mutations cause oral-facial-digital syndrome (PMID:38158857) and have been reported in constitutional aplastic anemia (PMID:35371815). ZRSR2 is a core component of the minor (U12) spliceosome, and its depletion causes widespread U12-type intron retention (PMID:25586593).
Under the ClinGen SVI PVS1 decision framework (PMC6185798), a frameshift variant in a gene with an established LOF disease mechanism is classified as PVS1 at very_strong strength. NMD is predicted as the premature termination codon occurs in exon 5 of 11.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting PM2 at moderate strength (allele frequency <0.1% per generic ACMG thresholds).
The variant has been observed once in a somatic cancer sample (COSMIC COSV57067023), consistent with its predicted loss-of-function effect, though this somatic observation is not directly applied to germline ACMG criteria.
No variant-specific functional studies, de novo observations, segregation data, or ClinVar classifications were identified for this variant.
Combined evidence: 1 Very_Strong (PVS1) + 1 Moderate (PM2) meets the generic ACMG/AMP Likely Pathogenic classification threshold (1 Very_Strong + 1 Moderate).
No criteria match.
Met · 2
PVS1 Very strongNM_005089.3:c.398_399del is a frameshift variant in exon 5 of 11, predicted to cause premature termination at codon 143 (p.Glu133GlyfsTer11), removing 340 of 483 amino acids including the zinc finger and RS-rich domains. NMD is predicted as the premature termination codon occurs more than 55 nucleotides upstream of the last exon-exon junction. ZRSR2 loss-of-function is an established germline disease mechanism supported by literature describing germline ZRSR2 mutations in oral-facial-digital syndrome and aplastic anemia. Under the ClinGen SVI PVS1 decision framework (PMC6185798), frameshift variants meeting the gene-level LOF gate are classified as PVS1 at very_strong strength. Details ▾Hide ▴
Evidence considered
- Frameshift variant (c.398_399del) predicted to cause p.Glu133GlyfsTer11
- Premature termination codon located in exon 5 of 11
- NMD expected
- Loss-of-function mechanism supported for ZRSR2 in germline disease
- ZRSR2 LOF causes U12-dependent splicing defects (PMID:25586593)
- Germline ZRSR2 variants cause oral-facial-digital syndrome (PMID:38158857)
- Germline ZRSR2 mutation reported in aplastic anemia/colon cancer case (PMID:35371815)
- ZRSR2 mutations cause minor spliceosomopathies (PMID:39761998)
Sources
PM2 ModerateNM_005089.3:c.398_399del is absent from all population databases queried, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). For a rare disease-associated gene on the X chromosome, complete absence from large population cohorts (<0.1% under non-VCEP generic ACMG) supports a pathogenic interpretation. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
Not met · 19 · evaluated, threshold not reached
PS2 No de novo observation data is available for NM_005089.3:c.398_399del. No proband narratives or confirmed parental testing results were provided. Details ▾Hide ▴
Still missing
- No de novo testing data available
PS3 No variant-specific functional data exists for NM_005089.3:c.398_399del. PMID:25586593 provides gene-level functional evidence that ZRSR2 loss-of-function disrupts U12-dependent splicing, but does not test or report this specific variant. The paper studied eight MDS patients with ZRSR2 nonsense/frameshift mutations via RNA-Seq and performed shRNA knockdown experiments; none of the specific mutations are listed as c.398_399del nor is codon 133 mentioned. This paper represents domain-level/gene-level mechanistic evidence appropriate for PVS1 and PM1 contexts, not PS3 variant-specific functional data. Details ▾Hide ▴
Evidence considered
- ZRSR2 LOF confirmed to disrupt U12-dependent splicing in cell lines and patient samples (PMID:25586593)
- No direct testing of NM_005089.3:c.398_399del or systematic range characterization including position 133
Still missing
- No variant-specific functional assay performed for c.398_399del
Sources
PS4 No case-control or statistical enrichment data is available for NM_005089.3:c.398_399del. The variant has been observed once in COSMIC (COSV57067023, somatic), but this does not constitute germline case-control evidence for PS4. Details ▾Hide ▴
Evidence considered
- COSMIC: observed once in somatic cancer (COSV57067023)
Still missing
- No germline case-control or enrichment data
PM1 Position p.Glu133 is not located within a statistically significant mutational hotspot (cancerhotspots.org: no significant residue-level enrichment). While the frameshift truncates most of the ZRSR2 protein including functionally characterized C-terminal domains (zinc finger at ~280-310, RS-rich domain), PM1 is typically assigned to missense variants within well-defined functional domains. The truncation evidence is more appropriately captured under PVS1. No specific functional domain boundary has been characterized at or immediately surrounding residue 133. Details ▾Hide ▴
Evidence considered
- Not a statistically significant hotspot (cancerhotspots.org)
- PMID:25586593 demonstrates ZRSR2 essential for U12 splicing but does not define positional domain boundaries
Sources
PM6 No de novo observation data is available for NM_005089.3:c.398_399del. No confirmed maternity/paternity testing results were reported. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 No segregation data is available for NM_005089.3:c.398_399del. No affected family members or co-segregation analyses were reported. Details ▾Hide ▴
Still missing
- No segregation data available
PP3 SpliceAI predicts no significant splice impact (max delta score = 0.02). REVEL and BayesDel scores are not applicable (variant is not an SNV). No HCI prior score is available. For a frameshift variant, the deleterious effect is inherent in the variant type and captured under PVS1; in silico evidence adds no additional support. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (no significant splice impact)
- REVEL/BayesDel not applicable (not SNV)
- HCI prior not available
Sources
PP4 No patient-specific phenotype or clinical information was provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for the gene/disease. Details ▾Hide ▴
Still missing
- No patient phenotype information provided
PP5 NM_005089.3:c.398_399del is absent from ClinVar. No reputable source has reported this variant as pathogenic. PP5 requires a ClinVar classification from a reputable source (ideally expert panel, 3-star or above). Details ▾Hide ▴
BA1 NM_005089.3:c.398_399del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
BS1 NM_005089.3:c.398_399del is absent from all population databases. The allele frequency is 0%, well below the BS1 threshold of >0.3% for non-VCEP generic ACMG. Details ▾Hide ▴
BS2 NM_005089.3:c.398_399del has not been observed in healthy adult individuals. BS2 requires observation of the variant in a healthy control inconsistent with disease penetrance — no such observation exists. Details ▾Hide ▴
Still missing
- Not observed in healthy controls
BS3 The only functional study available (PMID:25586593) demonstrates that ZRSR2 loss-of-function disrupts U12-dependent splicing, which supports a deleterious effect consistent with pathogenicity. There is no evidence from well-established functional studies showing a normal or benign effect of this variant on protein function or splicing. Details ▾Hide ▴
Evidence considered
- PMID:25586593: ZRSR2 LOF causes U12 splicing defects — consistent with pathogenic mechanism
Sources
BS4 No segregation data is available for NM_005089.3:c.398_399del. BS4 requires lack of segregation in affected family members — no family segregation analysis was performed. Details ▾Hide ▴
Still missing
- No segregation data
BP2 No observation of NM_005089.3:c.398_399del in trans with a known pathogenic variant in ZRSR2 or in cis with a pathogenic variant. BP2 requires such an observation to support a benign interpretation. Details ▾Hide ▴
Still missing
- No trans/cis observation data
BP4 SpliceAI predicts no significant splice impact (max delta = 0.02), but this computational evidence does not suggest a benign effect for a frameshift variant. The variant's truncating nature is inherently damaging; BP4 is typically reserved for missense variants where multiple lines of computational evidence suggest no impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (no significant splice impact)
- Frameshift variant — inherently damaging
- computational benign prediction not meaningful
Sources
BP5 No report of NM_005089.3:c.398_399del being found in a case with an alternate molecular basis for disease. BP5 requires an alternate pathogenic variant identified that explains the phenotype. Details ▾Hide ▴
Still missing
- No alternate molecular basis reported
BP6 NM_005089.3:c.398_399del is absent from ClinVar. No reputable source has reported this variant as benign or likely benign. Details ▾Hide ▴
PS5 No previously established pathogenic variant has been reported that causes the same protein change (p.Glu133GlyfsTer11) at this position. ClinVar contains no entries for NM_005089.3:c.398_399del or variants at the same codon. Details ▾Hide ▴
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANM_005089.3:c.398_399del is a 2-nucleotide deletion causing a frameshift; PS1 applies only to single-nucleotide variants where a different nucleotide change at the same position has been previously established as pathogenic. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped per adjudication instruction (trivially not_applicable). Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. NM_005089.3:c.398_399del is a 2-nucleotide frameshift deletion causing a premature stop codon (p.Glu133GlyfsTer11), which is an out-of-frame change assessed under PVS1, not PM4. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a different missense variant at the same residue that has been classified as pathogenic. NM_005089.3:c.398_399del is a frameshift deletion; no same-residue missense comparator semantics apply. The automated PM5 candidate harvesting system confirmed this variant is not eligible for classic PM5 analysis. Details ▾Hide ▴
Evidence considered
- Frameshift variant
- no same-residue missense comparators identified
Sources
pm5_candidates
PP2 N/APP2 applies specifically to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare. NM_005089.3:c.398_399del is a frameshift variant; PP2 does not apply to truncating variants. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants are the known disease mechanism. NM_005089.3:c.398_399del is itself a truncating (frameshift) variant, so BP1 does not apply. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_005089.3:c.398_399del is a 2-nucleotide frameshift deletion, not an in-frame change in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact and low nucleotide conservation. NM_005089.3:c.398_399del is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- ZRSR2
- Transcript
- NM_005089.3
- Coding (HGVS c.)
- NM_005089.3:c.398_399del
- Protein (HGVS p.)
- NP_005080.1:p.(Glu133GlyfsTer11)
- GRCh38
- chrX:15804193 AAG>A
- GRCh37
- chrX:15822316 AAG>A
- COSMIC
- COSV57067023
Gene diagram
Every interpreted variant in ZRSR2, mapped onto the exon structure of NM_005089.3. Select a row to find it on the plot.
ZRSR2NM_005089.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ZRSR2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no significant splice impact (max delta score = 0.02). REVEL and BayesDel scores are not applicable (variant is not an SNV). No HCI prior score is available. For a frameshift variant, the deleterious effect is inherent in the variant type and captured under PVS1; in silico evidence adds no additional support. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (no significant splice impact)
- REVEL/BayesDel not applicable (not SNV)
- HCI prior not available
Sources
BP4 SpliceAI predicts no significant splice impact (max delta = 0.02), but this computational evidence does not suggest a benign effect for a frameshift variant. The variant's truncating nature is inherently damaging; BP4 is typically reserved for missense variants where multiple lines of computational evidence suggest no impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (no significant splice impact)
- Frameshift variant — inherently damaging
- computational benign prediction not meaningful
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact and low nucleotide conservation. NM_005089.3:c.398_399del is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
1 paper record listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
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PMID 25586593 ↗Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome.Characterizes ZRSR2 as an essential component of the U12-dependent minor spliceosome. shRNA knockdown of ZRSR2 in cell lines and RNA-Seq of eight MDS patient bone marrow samples with ZRSR2 nonsense or frameshift mutations demonstrated specific U12-type intron retention, with U2-type splicing largely unaffected. Knockdown of ZRSR2 altered hematopoietic differentiation, reducing erythroid colonies and increasing myeloid differentiation. NM_005089.3:c.398_399del was not specifically mentioned in this paper.→ PVS1 Does not name this variant
Source detail
In MDS, somatic mutations in ZRSR2 occur across the entire length of the transcript, which is in contrast to mutational hotspots observed in SF3B1, SRSF2 and U2AF1. Moreover, nonsense, splice-site and frame-shift mutations in ZRSR2 gene frequently occur in males, suggesting a loss of function.
Location Results (Figure 2a — ZRSR2 mutant MDS samples); Discussion
Context shRNA knockdown in TF-1, K562, 293T cells; RNA-Seq of 8 MDS patient bone marrow samples with ZRSR2 mutations; minigene splicing assays
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
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_005089.3%3Ac.398_399del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-15822316-AAG-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-15804193-AAG-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/X-15804193-AAG-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005089.3%3Ac.398_…
- OncoKB ↗www.oncokb.org/gene/ZRSR2/E133Gfs*11
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=130005115
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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 does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57067023, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.