Final classification

Likely Pathogenic

PVS1PM2

ZRSR2

c.376C>T

p.Arg126Ter

This variant

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.

Transcript

NM_005089.3

HGVS · transcript:coding

NM_005089.3:c.376C>T

GRCh38

chrX:15804174 C>T

GRCh37

chrX:15822297 C>T

Generic ACMG/AMP 2015 final-classification combination rules (fallback), as indicated by final_classification_framework.json.

Classification rationale

PVS1PM2 Likely Pathogenic

ZRSR2 c.376C>T

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.¹ 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.² 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 ZRSR2.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.10.⁴

PVS1 + PM2 → Likely Pathogenic

1 cosmic ↗

2 gnomad_v4 ↗

3 pvs1_gene_context

4 spliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_005089.3 · variants mapped to exon structure

ZRSR2 NM_005089.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 18 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 very_strong review Pathogenic

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.

ZRSR2 loss of function supported as germline disease mechanismVariant bucket: nonsenseProtein consequence: NP_005080.1:p.(Arg126Ter) / p.(R126*)

pvs1_generic_framework ↗

PM2 moderate review Pathogenic

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 v2.1 absentgnomAD v4.1 absentObserved AF 0 < 0.1% threshold

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 2 not met · 16 not assessed

Pathogenic

PS2 No confirmed de novo data with parental testing were identified, so PS2 cannot be assessed from the available evidence.

PS3 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.

PS4 This variant has been observed in somatic cancers in COSMIC (COSV57066630, n=5), but no germline case-control or case-enrichment data were identified.

PM1 Available evidence does not show that this variant lies in a mutational hotspot or a well-established critical functional domain without benign variation.

PM3 No data were identified showing this variant in trans with another pathogenic variant in an affected individual, so PM3 cannot be assessed.

PM6 No assumed de novo occurrence without confirmed parental testing was identified, so PM6 cannot be assessed.

PP1 No segregation data were identified, so PP1 cannot be applied.

PP4 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 No reputable source classification for this specific variant was identified that could be considered under PP5, and the variant is absent from ClinVar.

Benign

BA1 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%.

BS1 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%.

BS2 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 A general ZRSR2 functional paper was identified, but no well-established assay showing that this specific variant has no damaging effect was identified.

BS4 No family data were identified showing lack of segregation with disease, so BS4 cannot be assessed.

BP2 No phase information or second-variant data were identified to support BP2, so this criterion cannot be assessed.

BP3 No evidence was identified showing that this variant lies in a repetitive region without known function, so BP3 cannot be assessed.

BP5 No alternate molecular diagnosis or alternate established cause for the phenotype was provided, so BP5 cannot be assessed.

BP6 No reputable source classification reporting this variant as benign was identified, and the variant is absent from ClinVar.

N/A · 8 PS1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP4 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57066630, n = 5 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

5papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

PMID 25645650

PMID 25645650 ↗

Found