NM_005089.3:c.758T>C

ZRSR2 · NP_005080.1:p.(Val253Ala) · NM_005089.3

GRCh37: chrX:15834000 T>C · GRCh38: chrX:15815877 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.(Val253Ala)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_005089.3:c.758T>C (p.Val253Ala) is a missense variant in ZRSR2, a gene encoding a component of the minor spliceosome that is implicated in myelodysplastic syndromes, spliceosomopathies, and oral-facial-digital syndrome.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting level.

The variant is absent from ClinVar, COSMIC, and CancerHotspots.org; no variant-specific functional data, segregation data, or de novo observations are available.

SpliceAI predicts no significant splicing impact (max delta score 0.04). BayesDel add score is 0.527 (above the 0.27 damaging threshold), but as the sole predictor available, it does not meet the PP3 multiple-lines requirement.

No publications in the literature packet mention the specific variant NM_005089.3:c.758T>C (p.Val253Ala). Five PMIDs reviewed for ZRSR2 gene-level context did not contain variant-specific data.

PVS1 is not applicable as this is a missense variant not falling into the null-variant buckets of the ClinGen PVS1 decision framework (PMC6185798).

Overall classification is limited by paucity of evidence. Only one supporting-level criterion (PM2) is met, which is insufficient to reach a Likely Pathogenic or Pathogenic classification under generic ACMG/AMP 2015 combination rules. No benign criteria are met.

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	NM_005089.3:c.758T>C is a missense variant (p.Val253Ala). It does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The generic PVS1 decision framework (PMC6185798) was not triggered.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No ClinVar entry exists for this variant or any variant at this residue; no comparator nucleotide change yielding the same amino acid change is available. PS1 requires a known pathogenic variant with the same amino acid change but different nucleotide change.	clinvar
PS2	Not met	No de novo confirmation data are available for this variant. PS2 requires a de novo observation with both maternity and paternity confirmed.
PS3	Not met	No variant-specific functional data exist for NM_005089.3:c.758T>C (p.Val253Ala). OncoKB classifies this alteration as Unknown Oncogenic Effect with no curated functional evidence. No publications with functional characterization of this variant were identified.	oncokb
PS4	Not met	No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls are available.
PS5	Not met	No established pathogenic variant with the same amino acid change (p.Val253Ala) from a different nucleotide change is recorded in ClinVar. PS5 requires a previously established pathogenic variant at the same residue regardless of nucleotide change.	clinvar
PM1	Not met	Residue 253 does not lie in a statistically significant cancer hotspot per CancerHotspots.org. No published functional domain characterization confirms that position 253 resides within a well-defined critical functional domain. The ZRSR2 zinc finger domains are located N-terminal to this position, and without specific domain boundary evidence encompassing residue 253, PM1 cannot be applied.
PM2	Met	NM_005089.3:c.758T>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). The variant allele frequency is well below the 0.1% threshold for PM2 application in a gene without a CSPEC-specific frequency cutoff.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants with a pathogenic classification were identified in ClinVar. The automated PM5 candidate search returned zero candidates.	pm5_candidates clinvar
PM6	Not met	No de novo observation reported for this variant. PM6 requires a de novo observation without confirmation of paternity and maternity.
PP1	Not met	No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2	Not met	ZRSR2 does not have an HCI prior score or externally calculated missense constraint metric available. Without evidence that ZRSR2 has a low rate of benign missense variation (z-score or equivalent), PP2 cannot be applied.
PP3	Not met	PP3 requires multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no significant splicing impact (max delta score 0.04). BayesDel add score is 0.527, which is above the 0.27 damaging threshold, but this is the sole computational predictor available; REVEL was not found for this variant. A single computational line does not meet the PP3 multiple-lines requirement.	spliceai bayesdel
PP4	Not met	No patient phenotype or family history data are available for adjudication. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	This variant is absent from ClinVar. PP5 requires a reputable source (ClinVar 3-star expert panel or higher) to have classified the variant as pathogenic. No ClinVar entry exists for NM_005089.3:c.758T>C.	clinvar
BA1	Not met	The variant is absent from all gnomAD datasets. Allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from all gnomAD datasets. Allele frequency is 0%, well below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of this variant in healthy adult controls beyond population databases is available. BS2 requires observation in a healthy adult individual for a fully penetrant disorder, or absence of phenotype specificity data.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a benign effect for this variant. No functional data of any kind were identified for p.Val253Ala.	oncokb
BS4	Not met	No family segregation or linkage data are available to demonstrate lack of segregation with disease.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. ZRSR2 germline disease has been associated with variation broadly (PMID:38158857 links ZRSR2 variation, not exclusively truncating, to oral-facial-digital syndrome). There is insufficient evidence that ZRSR2-associated disease is primarily caused by truncating variants alone.	pvs1_gene_context
BP2	Not met	BP2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in a recessive disorder. No such observations are available.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. SpliceAI max delta score is 0.04 (no predicted splicing impact), but BayesDel add score is 0.527, which is above the damaging threshold. The in silico evidence is conflicted and does not meet the BP4 multiple-lines requirement for a benign computational consensus.	spliceai bayesdel
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease is available. BP5 requires that the variant be found in an individual with a clear alternate genetic cause of their phenotype.
BP6	Not met	This variant is absent from ClinVar. BP6 requires a reputable source to have classified the variant as benign. No ClinVar entry exists for NM_005089.3:c.758T>C.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants. NM_005089.3:c.758T>C is a missense variant (p.Val253Ala), not a synonymous variant.
BP3	N/A	This is a substitution variant, not an in-frame deletion/insertion in a repetitive region.
PM3	N/A	PM3 applies to recessive disorders with biallelic observations. No biallelic data or established recessive inheritance for ZRSR2 is available.
PM4	N/A	PM4 applies to protein-length changes from in-frame deletions/insertions or stop-loss variants. This is a missense substitution.

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