Classification rationale

PM2PM4 BP4 VUS

ZRSR2 c.983_984insGAA in_frame_indel_unknown · exon 11

PM2 (Supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases. PM4 (Moderate): in-frame insertion p.(Phe328delinsLeuAsn) changes protein length in the conserved, non-repeat CCCH zinc-finger region. BP4 (Supporting): SpliceAI max delta 0.05 predicts no splice impact, well below the 0.2 threshold. Together these criteria reach no ACMG/AMP classification threshold, yielding a final classification of Uncertain Significance (VUS).

PM2 + PM4 + BP4 → VUS

Gene diagram · NM_005089.3 · variants mapped to exon structure

ZRSR2 NM_005089.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 18 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): absent from the gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population datasets.

gnomAD v2.1 queried X-15840899-T-TGAA and found it absent.gnomAD v4.1 and gnomAD-Canada v1.0 queried X-15822776-T-TGAA and found it absent.No ZRSR2 ClinGen VCEP or gene-specific population-frequency specification was retrieved for this case; the case framework specifies generic ACMG/AMP fallback.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PM4 moderate Pathogenic

Met (moderate): in-frame insertion p.(Phe328delinsLeuAsn) changes protein length (+1 residue) in the non-repeat CCCH zinc-finger region.

Variant normalization (Mutalyzer and VariantValidator, recorded in prefetch/case_summary): NM_005089.3:c.983_984insGAA is an in-frame 3-nucleotide insertion predicting NP_005080.1:p.(Phe328delinsLeuAsn), i.e., Phe328 replaced by Leu-Asn with a net protein length change of +1 residue (reference 483 aa to predicted 484 aa).Exon context: the variant maps to exon 11, the terminal exon of NM_005089.3 (VariantValidator variant_exonic_positions), so the in-frame transcript is not subject to NMD and the predicted protein-level change is expressed.SpliceAI Lookup reports max delta score 0.05 for this variant, predicting no significant splice impact; this supports the in-frame protein length change as the operative consequence rather than aberrant splicing.

spliceai ↗

✓

BP4 supporting Benign

Met (supporting): SpliceAI max delta 0.05, well below the 0.2 splice-altering threshold, predicts no splice impact.

SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).' (source: spliceai)SpliceAI raw scores: DS_AG=0.05, DS_AL=0.016, DS_DG=0.0, DS_DL=0.008, max_delta_score=0.05, well below the 0.2 pathogenic-supporting cutoff (source: spliceai)Jaganathan KK et al., 'Predicting Splicing from Primary Sequence with Deep Learning', Cell 2019, PMID 30661751 -- source of the 0.2/0.5/0.8 SpliceAI delta-score calibration thresholds used to interpret the max delta of 0.05 as non-significant

spliceai ↗

Assessed · not applied · 6 not met · 12 not assessed

Pathogenic

PS2 Insufficient evidence: no proband phenotype or parental testing data were available to establish a de novo occurrence.

PS3 Insufficient evidence: no validated functional assay data for this specific variant were available.

PS4 Insufficient evidence: no affected-case series, case-control, or enrichment data for this exact variant were retrieved.

PM3 Insufficient evidence: no affected proband with a second pathogenic variant or recessive disease context was documented.

PM6 Insufficient evidence: no proband or parental testing data were available to assume a de novo occurrence.

PP1 Insufficient evidence: no pedigree or relative genotypes were available to evaluate cosegregation.

PP3 Not met: SpliceAI max delta 0.05 is far below the 0.2 pathogenic-supporting threshold, with no other computational signal.

PP4 Insufficient evidence: no proband phenotype or disease indication was supplied to assess phenotype specificity.

PP5 Not met: the exact variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.

Benign

BA1 Not met: absent from all queried population databases, so the stand-alone benign frequency threshold is not reached.

BS1 Not met: the variant is absent from population databases, so no allele frequency exceeds the benign threshold.

BS2 Insufficient evidence: population databases report no observations in unaffected adults from which to assess.

BS3 Insufficient evidence: no functional assay data showing normal function for this variant were available.

BS4 Insufficient evidence: no affected non-carriers or unaffected carriers were documented to evaluate lack of segregation.

BP2 Insufficient evidence: no confirmed in-cis co-occurrence with a pathogenic variant was documented.

BP3 Not met: the variant lies in the functional CCCH zinc-finger domain, not a repeat region without known function.

BP5 Insufficient evidence: no molecular testing results were supplied to determine whether an alternate cause explains the phenotype.

BP6 Not met: the exact variant is absent from ClinVar, so no expert-panel benign assertion exists.

N/A · 7 PVS1 · PS1 · PM1 · PM5 · PP2 · BP1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ZRSR2, a splicing factor, is altered in various hematological malignancies.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots