NM_005089.3:c.617T>C

ZRSR2 · NP_005080.1:p.(Phe206Ser) · NM_005089.3

GRCh37: chrX:15833859 T>C · GRCh38: chrX:15815736 T>C

Gene: ZRSR2 Transcript: NM_005089.3

Final call

VUS

PM2 supporting

Variant details

Gene

ZRSR2

Transcript

NM_005089.3

Protein

NP_005080.1:p.(Phe206Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

Available curated review did not identify variant-specific reviewed functional evidence for this variant.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This variant is a missense substitution, p.(Phe206Ser), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice variants. Although germline loss of function is a supported disease mechanism for ZRSR2, available evidence does not support applying PVS1 to this specific variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No established pathogenic or likely pathogenic variant causing the same amino acid change was identified, so PS1 was not assessed.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 was not assessed.	clinvar
PS3	Not assessed	No well-established functional study demonstrating a damaging effect of this specific variant was identified, so PS3 was not assessed.	oncokb
PS4	Not met	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.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	Available evidence does not support that residue 206 lies in a statistically significant hotspot or a well-established critical functional region without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this position.	hotspots
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic variant in an affected individual, so PM3 was not assessed.
PM4	N/A	This variant is a missense substitution and does not cause a protein length change, so PM4 is not applicable.
PM5	N/A	PM5 was not applied because no qualified same-residue pathogenic comparator was identified, and available review materials could not safely confirm classic same-residue PM5 semantics for this case.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without parental confirmation was identified for this variant, so PM6 was not assessed.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	clinvar
PP2	Not assessed	Available evidence does not establish that missense variation is a common disease mechanism for ZRSR2, so PP2 was not assessed.	pvs1_gene_context
PP3	Not met	Computational evidence is insufficiently consistent to support PP3. BayesDel predicts a deleterious effect with a score of 0.563308, but SpliceAI predicts no significant splice impact with a maximum delta score of 0.09, and no REVEL score was available.	bayesdel spliceai
PP4	Not assessed	No phenotype-specific clinical evidence was provided to show a presentation highly specific for a ZRSR2-related disorder, so PP4 was not assessed.
PP5	Not assessed	No reputable-source pathogenic classification without accessible supporting evidence was identified, so PP5 was not assessed.	clinvar
BA1	Not met	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%. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	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%. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not met	This variant has not been observed in population databases, so occurrence in healthy individuals does not support BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing normal function for this specific variant was identified, so BS3 was not assessed.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 was not assessed.	clinvar
BP1	Not assessed	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.	pvs1_gene_context
BP2	Not assessed	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.
BP3	N/A	This variant is not an in-frame deletion or insertion within a repetitive region, so BP3 is not applicable.
BP4	Not met	Computational evidence does not support BP4. SpliceAI predicts no significant splice impact with a maximum delta score of 0.09, but BayesDel is positive at 0.563308 for a deleterious missense effect, so the available in silico evidence is not uniformly benign.	spliceai bayesdel
BP5	Not assessed	No evidence was identified showing that an alternate molecular cause fully explains the observed phenotype, so BP5 was not assessed.
BP6	Not assessed	No reputable-source benign classification without accessible supporting evidence was identified, so BP6 was not assessed.	clinvar
BP7	N/A	This variant is a missense substitution rather than a synonymous or intronic variant, so BP7 is not applicable.

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