NM_005089.3:c.812A>G

ZRSR2 · NP_005080.1:p.(Tyr271Cys) · NM_005089.3

GRCh37: chrX:15836750 A>G · GRCh38: chrX:15818627 A>G

Gene: ZRSR2 Transcript: NM_005089.3

Final call

VUS

PM2 supporting

Variant details

Gene

ZRSR2

Transcript

NM_005089.3

Protein

NP_005080.1:p.(Tyr271Cys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The ZRSR2 c.812A>G (p.Tyr271Cys; p.Y271C) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting PM2 at supporting strength.

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.

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.

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	Not met	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. Available evidence therefore does not support applying PVS1.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified that this amino acid change has a previously established pathogenic amino acid substitution at the same residue.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant.	clinvar
PS3	Not assessed	No published well-established functional study was identified for p.Tyr271Cys (p.Y271C) showing a damaging effect.	oncokb clinvar
PS4	Not met	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. Available evidence does not support PS4.	clinvar
PM1	Not met	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. Cancer Hotspots did not identify a statistically significant hotspot at this residue, and the hotspot review was flagged as uncertain.	hotspots
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is intended for recessive disorders with detected variants in trans, and that evidence context was not identified for this case.
PM4	N/A	PM4 applies to protein length changes from in-frame insertions/deletions or stop-loss variants, and this variant is a missense substitution.
PM5	Not assessed	No evidence was identified that a different pathogenic missense change at codon 271 has been established.	clinvar
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	Not assessed	Available evidence does not establish a gene-specific missense-constraint pattern that would support PP2 for this variant.	final_classification_framework
PP3	Not assessed	Computational evidence is limited and mixed for this missense change. SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, while BayesDel is 0.588005; without additional concordant missense predictors, these data do not provide sufficient support to apply PP3.	spliceai bayesdel
PP4	Not assessed	No phenotype-specific clinical evidence was provided to show a presentation highly specific for a single-gene ZRSR2 disorder.
PP5	Not assessed	No reputable source classification suitable for PP5 use was identified for this variant.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and is therefore well below the benign stand-alone threshold of 1%. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and therefore does not exceed the benign strong frequency threshold of 0.3%. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a manner sufficient to support BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No published well-established functional study was identified for p.Tyr271Cys (p.Y271C) showing normal protein function or no damaging effect.	oncokb
BS4	Not assessed	No family data were identified showing lack of segregation between this variant and disease.	clinvar
BP1	Not assessed	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.	pvs1_gene_context final_classification_framework
BP2	Not assessed	No phase information or second-variant context was identified to assess BP2.
BP3	N/A	BP3 applies to in-frame insertions or deletions in repetitive regions without known function, and this variant is a missense substitution.
BP4	Not assessed	Available computational evidence does not support a benign interpretation. SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, but BayesDel is 0.588005 and does not support BP4; overall, the computational data are not sufficient to apply BP4.	spliceai bayesdel
BP5	Not assessed	No alternate molecular diagnosis or other established cause of disease was provided to assess BP5.
BP6	Not assessed	No reputable source reported this variant as benign or likely benign in the reviewed materials.	clinvar
BP7	N/A	BP7 is intended for synonymous or certain noncoding variants with no predicted splice impact, and this variant is a missense substitution.	spliceai

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.