Classification rationale

PM2 VUS

ZRSR2 c.812A>G

The ZRSR2 c.812A>G (p.Tyr271Cys; p.Y271C) variant has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting PM2 at supporting strength.² Generic PVS1 is not supported because this is a missense substitution rather than a predicted null variant, although gene-level evidence supports loss of function as a disease mechanism for ZRSR2.³ Computational evidence is not sufficient for a definitive missense prediction: SpliceAI predicts no significant splice effect with a maximum delta score of 0.08, while BayesDel is 0.588005.⁴

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗

4 spliceai ↗bayesdel

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 · 23 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 absent from gnomAD v4.1, which is below the non-VCEP rarity threshold of 0.1% and supports PM2 at supporting strength.

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

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 5 not met · 18 not assessed

Pathogenic

PVS1 ZRSR2 loss of function is an established disease mechanism, but NM_005089.3:c.812A>G (p.Tyr271Cys; p.Y271C) is a missense substitution in exon 9 and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1/2 splice variants.

PS1 No evidence was identified that this amino acid change has a previously established pathogenic amino acid substitution at the same residue.

PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant.

PS3 No published well-established functional study was identified for p.Tyr271Cys (p.Y271C) showing a damaging effect.

PS4 This variant has not been reported in ClinVar, and no case-control or case-enrichment data were identified showing that p.Tyr271Cys (p.Y271C) is more common in affected individuals than in controls.

PM1 Available evidence does not show that p.Tyr271Cys (p.Y271C) lies in a well-established mutational hotspot or a critical functional domain without benign variation.

PM5 No evidence was identified that a different pathogenic missense change at codon 271 has been established.

PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 Available evidence does not establish a gene-specific missense-constraint pattern that would support PP2 for this variant.

PP3 Computational evidence is limited and mixed for this missense change.

PP4 No phenotype-specific clinical evidence was provided to show a presentation highly specific for a single-gene ZRSR2 disorder.

PP5 No reputable source classification suitable for PP5 use was identified for this variant.

Benign

BA1 This variant is absent from gnomAD v2.1 and v4.1 and is therefore well below the benign stand-alone threshold of 1%.

BS1 This variant is absent from gnomAD v2.1 and v4.1 and therefore does not exceed the benign strong frequency threshold of 0.3%.

BS2 No evidence was identified showing this variant in healthy adult individuals in a manner sufficient to support BS2.

BS3 No published well-established functional study was identified for p.Tyr271Cys (p.Y271C) showing normal protein function or no damaging effect.

BS4 No family data were identified showing lack of segregation between this variant and disease.

BP1 Although ZRSR2 loss of function is a recognized disease mechanism, the reviewed material does not provide a validated gene-specific framework showing that missense variation is consistently benign enough to support BP1 for this variant.

BP2 No phase information or second-variant context was identified to assess BP2.

BP4 Available computational evidence does not support a benign interpretation.

BP5 No alternate molecular diagnosis or other established cause of disease was provided to assess BP5.

BP6 No reputable source reported this variant as benign or likely benign in the reviewed materials.

N/A · 4 PM3 · PM4 · 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 = 0.08). BayesDel score = 0.588005.

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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