NM_005089.3:c.376C>T

ZRSR2 · NP_005080.1:p.(Arg126Ter) · NM_005089.3

GRCh37: chrX:15822297 C>T · GRCh38: chrX:15804174 C>T

Gene: ZRSR2 Transcript: NM_005089.3

Final call

Likely Pathogenic

PVS1_VeryStrong PM2_Moderate

Variant details

Gene

ZRSR2

Transcript

NM_005089.3

Protein

NP_005080.1:p.(Arg126Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The ZRSR2 c.376C>T (p.Arg126Ter) variant has been observed in somatic cancers in COSMIC (COSV57066630, n=5) and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed population frequency of 0 that is below the 0.1% PM2 rarity threshold.

This is an early truncating variant in exon 5 of 11, predicted to create p.Arg126Ter at codon 126 of 483, and available gene-level literature supports loss of function as a disease mechanism for ZRSR2.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.10.

Final determination: PVS1 at very strong strength together with PM2 at moderate strength meets the ACMG/AMP 2015 combination for Likely Pathogenic (1 very strong and 1 moderate).

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	Met	This variant is a nonsense change, NM_005089.3:c.376C>T, predicted to create p.(Arg126Ter) in exon 5 of 11 and truncate the protein at codon 126 of 483. Published germline disease literature supports loss of function as a disease mechanism for ZRSR2, and this early truncating variant is expected to undergo nonsense-mediated decay under the generic ClinGen SVI PVS1 framework, supporting PVS1 at very strong strength.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework prefetch
PS1	N/A	PS1 applies when a different nucleotide change results in the same amino acid change. This variant is a nonsense change, and no alternate nucleotide substitution producing the same established pathogenic amino acid change was identified.	prefetch clinvar
PS2	Not assessed	No confirmed de novo data with parental testing were identified, so PS2 cannot be assessed from the available evidence.
PS3	Not assessed	A ZRSR2 functional paper was identified, but no well-established functional study specific to NM_005089.3:c.376C>T or p.(Arg126Ter) was identified. Available evidence therefore does not support applying PS3 at this time.	PMID:25586593 literature_pass
PS4	Not assessed	This variant has been observed in somatic cancers in COSMIC (COSV57066630, n=5), but no germline case-control or case-enrichment data were identified. Somatic observations alone do not establish increased prevalence in affected individuals compared with controls for PS4.	cosmic literature_pass
PM1	Not assessed	Available evidence does not show that this variant lies in a mutational hotspot or a well-established critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot for this residue, and the hotspot review was flagged for human review.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the default PM2 rarity threshold of 0.1%. This rarity supports PM2.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with another pathogenic variant in an affected individual, so PM3 cannot be assessed.
PM4	N/A	PM4 is intended for protein length changes caused by in-frame indels or stop-loss variants. This variant is a nonsense change and is better addressed by PVS1 rather than PM4.	prefetch pvs1_variant_assessment
PM5	N/A	PM5 applies to a novel missense change at a residue where a different pathogenic missense change has been seen. This variant is not missense, so PM5 does not apply.	prefetch
PM6	Not assessed	No assumed de novo occurrence without confirmed parental testing was identified, so PM6 cannot be assessed.
PP1	Not assessed	No segregation data were identified, so PP1 cannot be applied.
PP2	N/A	PP2 is intended for missense variants in genes with a low rate of benign missense variation and where missense variation is a common disease mechanism. This variant is a nonsense change, so PP2 does not apply.	prefetch
PP3	N/A	SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.10, but the primary consequence is a nonsense change rather than a predicted splice-altering variant. Computational evidence was therefore not used to apply PP3.	spliceai prefetch
PP4	Not assessed	No patient phenotype data were provided that would establish a highly specific clinical presentation for a single-gene disorder caused by ZRSR2, so PP4 cannot be assessed.
PP5	Not assessed	No reputable source classification for this specific variant was identified that could be considered under PP5, and the variant is absent from ClinVar.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0, which is below the benign BA1 threshold of 1%. BA1 is therefore not met.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0, which is below the BS1 threshold of 0.3%. BS1 is therefore not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a context where full penetrance would be expected, so BS2 cannot be assessed.
BS3	Not assessed	A general ZRSR2 functional paper was identified, but no well-established assay showing that this specific variant has no damaging effect was identified. BS3 is therefore not supported.	PMID:25586593 literature_pass
BS4	Not assessed	No family data were identified showing lack of segregation with disease, so BS4 cannot be assessed.
BP1	N/A	BP1 applies to a missense variant in a gene where truncating variants are primarily responsible for disease. This variant is a nonsense change, so BP1 does not apply.	prefetch
BP2	Not assessed	No phase information or second-variant data were identified to support BP2, so this criterion cannot be assessed.
BP3	Not assessed	No evidence was identified showing that this variant lies in a repetitive region without known function, so BP3 cannot be assessed.
BP4	N/A	SpliceAI predicts no significant splice impact with a maximum delta score of 0.10, but this variant is a nonsense change and the computational result does not provide benign evidence against the truncating effect. BP4 was therefore not applied.	spliceai prefetch
BP5	Not assessed	No alternate molecular diagnosis or alternate established cause for the phenotype was provided, so BP5 cannot be assessed.
BP6	Not assessed	No reputable source classification reporting this variant as benign was identified, and the variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous variants or intronic variants with no predicted splice impact. This variant is a nonsense coding change, so BP7 does not apply.	prefetch spliceai

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