Variant classification summary

NM_005089.3:c.983_984insGAA

ZRSR2 · NP_005080.1:p.(Phe328delinsLeuAsn) · NM_005089.3

GRCh37: chrX:15840899 T>TGAA · GRCh38: chrX:15822776 T>TGAA

Gene: ZRSR2 Transcript: NM_005089.3

Final call

VUS

PM2 supporting PM4 moderate BP4 supporting

Variant details

Gene

ZRSR2

Transcript

NM_005089.3

Protein

NP_005080.1:p.(Phe328delinsLeuAsn)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases.

2

PM4 (Moderate): in-frame insertion p.(Phe328delinsLeuAsn) changes protein length in the conserved, non-repeat CCCH zinc-finger region.

3

BP4 (Supporting): SpliceAI max delta 0.05 predicts no splice impact, well below the 0.2 threshold.

4

Together these criteria reach no ACMG/AMP classification threshold, yielding a final classification of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback combination rules: the applied evidence (1 moderate + 1 supporting pathogenic, 1 supporting benign) does not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign threshold, 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	Not applicable: this in-frame insertion does not trigger nonsense-mediated decay, truncation, or canonical splice disruption.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: no amino acid change exists at this position to compare against a previously established pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Insufficient evidence: no proband phenotype or parental testing data were available to establish a de novo occurrence.	generic_acmg_combination_rules
PS3	Not assessed	Insufficient evidence: no validated functional assay data for this specific variant were available.
PS4	Not assessed	Insufficient evidence: no affected-case series, case-control, or enrichment data for this exact variant were retrieved.
PM1	N/A	Not applicable: no altered residue exists to evaluate for mutational hot-spot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (supporting): absent from the gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population datasets.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Insufficient evidence: no affected proband with a second pathogenic variant or recessive disease context was documented.	final_classification_framework generic_acmg_combination_rules
PM4	Met	Met (moderate): in-frame insertion p.(Phe328delinsLeuAsn) changes protein length (+1 residue) in the non-repeat CCCH zinc-finger region.	generic_acmg_combination_rules pvs1_variant_assessment spliceai
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a different pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Insufficient evidence: no proband or parental testing data were available to assume a de novo occurrence.	generic_acmg_combination_rules
PP1	Not assessed	Insufficient evidence: no pedigree or relative genotypes were available to evaluate cosegregation.	generic_acmg_combination_rules
PP2	N/A	Not applicable: applies to missense variants, and this variant is an in-frame insertion.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.05 is far below the 0.2 pathogenic-supporting threshold, with no other computational signal.	spliceai
PP4	Not assessed	Insufficient evidence: no proband phenotype or disease indication was supplied to assess phenotype specificity.
PP5	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: absent from all queried population databases, so the stand-alone benign frequency threshold is not reached.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from population databases, so no allele frequency exceeds the benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Insufficient evidence: population databases report no observations in unaffected adults from which to assess.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Insufficient evidence: no functional assay data showing normal function for this variant were available.
BS4	Not assessed	Insufficient evidence: no affected non-carriers or unaffected carriers were documented to evaluate lack of segregation.	generic_acmg_combination_rules
BP1	N/A	Not applicable: applies to missense variants in truncation-causing genes, and this is an in-frame insertion.	generic_acmg_combination_rules
BP2	Not assessed	Insufficient evidence: no confirmed in-cis co-occurrence with a pathogenic variant was documented.	final_classification_framework generic_acmg_combination_rules
BP3	Not met	Not met: the variant lies in the functional CCCH zinc-finger domain, not a repeat region without known function.	generic_acmg_combination_rules pvs1_variant_assessment
BP4	Met	Met (supporting): SpliceAI max delta 0.05, well below the 0.2 splice-altering threshold, predicts no splice impact.	spliceai
BP5	Not assessed	Insufficient evidence: no molecular testing results were supplied to determine whether an alternate cause explains the phenotype.
BP6	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: applies only to synonymous variants, and this variant alters the encoded protein sequence.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.