Classification rationale

PM2 VUS

ZRSR2 c.617T>C

The ZRSR2 c.617T>C (p.Phe206Ser; p.F206S) variant has not been reported in ClinVar and does not lie in a statistically significant hotspot.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the 0.1% PM2 threshold.² Available curated review did not identify variant-specific reviewed functional evidence for this variant.³ In silico evidence is mixed: BayesDel is positive at 0.563308, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.09, so computational findings do not currently support PP3 or BP4.⁴

PM2 → VUS

1 clinvar ↗hotspots ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 oncokb ↗

4 bayesdelspliceai ↗

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.

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

ZRSR2 NM_005089.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 22 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 · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the non-VCEP PM2 threshold of 0.1%. This supports rarity in the general population.

Absent from gnomAD v2.1Absent from gnomAD v4.1

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 7 not met · 15 not assessed

Pathogenic

PS1 No established pathogenic or likely pathogenic variant causing the same amino acid change was identified, so PS1 was not assessed.

PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 was not assessed.

PS3 No well-established functional study demonstrating a damaging effect of this specific variant was identified, so PS3 was not assessed.

PS4 No enrichment of this variant in affected individuals was identified, and no unrelated case series or case-control data were found to support increased prevalence in affected individuals over controls.

PM1 Available evidence does not support that residue 206 lies in a statistically significant hotspot or a well-established critical functional region without benign variation.

PM3 No data were identified showing this variant in trans with a pathogenic variant in an affected individual, so PM3 was not assessed.

PM6 No assumed de novo occurrence without parental confirmation was identified for this variant, so PM6 was not assessed.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

PP2 Available evidence does not establish that missense variation is a common disease mechanism for ZRSR2, so PP2 was not assessed.

PP3 Computational evidence is insufficiently consistent to support PP3.

PP4 No phenotype-specific clinical evidence was provided to show a presentation highly specific for a ZRSR2-related disorder, so PP4 was not assessed.

PP5 No reputable-source pathogenic classification without accessible supporting evidence was identified, so PP5 was not assessed.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the BA1 threshold of 1%.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the BS1 threshold of 0.3%.

BS2 This variant has not been observed in population databases, so occurrence in healthy individuals does not support BS2.

BS3 No well-established functional study showing normal function for this specific variant was identified, so BS3 was not assessed.

BS4 No non-segregation data were identified for this variant, so BS4 was not assessed.

BP1 Available evidence does not sufficiently establish that missense variants in ZRSR2 are generally less likely to be disease-causing than truncating variants, so BP1 was not assessed.

BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant, so BP2 was not assessed.

BP4 Computational evidence does not support BP4.

BP5 No evidence was identified showing that an alternate molecular cause fully explains the observed phenotype, so BP5 was not assessed.

BP6 No reputable-source benign classification without accessible supporting evidence was identified, so BP6 was not assessed.

N/A · 5 PVS1 · PM4 · PM5 · BP3 · 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.

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 v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). BayesDel score = 0.563308.

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

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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