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ZRSR2c.376C>TLikely pathogenic
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Variant interpretation report

ZRSR2 c.376C>T, p.(Arg126Ter)

NM_005089.3:c.376C>T NP_005080.1:p.(Arg126Ter) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About ZRSR2

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

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.

PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 2 not met · 16 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 2

PVS1 Very strongThis 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. Details ▾Hide ▴
Rule
Generic ClinGen SVI PVS1 framework for a nonsense variant in a gene with established loss-of-function mechanism.
Evidence considered
  • ZRSR2 loss of function supported as germline disease mechanism
  • Variant bucket: nonsense
  • Protein consequence: NP_005080.1:p.(Arg126Ter) / p.(R126*)
  • Exon position: exon 5 of 11
  • CDS length 1449 bp; predicted stop at codon 126 of 483
Still missing
  • Transcript relevance should be confirmed clinically because no gene-specific PVS1 specification was available.
  • No exon-level rescue or alternative transcript data were provided.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗prefetch3537181538158857397619982564565030977107
PM2 ModerateThis 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. Details ▾Hide ▴
Rule
PM2 is met when the variant is absent or at extremely low frequency in population databases and remains below the rarity threshold.
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 absent
  • Observed AF 0 < 0.1% threshold
Still missing
  • Population-specific counts were not provided beyond absence in the queried gnomAD datasets.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 2 · evaluated, threshold not reached

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%. BA1 is therefore not met. Details ▾Hide ▴
Rule
BA1 requires an allele frequency above the benign stand-alone threshold.
Evidence considered
  • Observed AF 0 < 1% BA1 threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗
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%. BS1 is therefore not met. Details ▾Hide ▴
Rule
BS1 requires an allele frequency greater than expected for the disorder.
Evidence considered
  • Observed AF 0 < 0.3% BS1 threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 16 · no assessment recorded

PS2 No confirmed de novo data with parental testing were identified, so PS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
PS2 requires a confirmed de novo occurrence in a patient with the disease and no family history.
Still missing
  • Parental testing and family structure were not provided.
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. Available evidence therefore does not support applying PS3 at this time. Details ▾Hide ▴
Rule
PS3 requires well-established functional studies supportive of a damaging effect for the specific variant.
Evidence considered
  • Functional literature identified for ZRSR2 generally
  • No variant-specific assay evidence for p.(Arg126Ter)
Still missing
  • No variant-specific validated functional assay result was identified.
Sources
PMID:25586593 ↗literature_pass25586593
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. Somatic observations alone do not establish increased prevalence in affected individuals compared with controls for PS4. Details ▾Hide ▴
Rule
PS4 requires significantly increased prevalence in affected individuals compared with controls.
Evidence considered
  • COSMIC somatic count 5
  • No germline database or case-enrichment evidence identified
Still missing
  • No germline case series or case-control enrichment study was identified.
Sources
cosmic ↗literature_pass
PM1 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. Details ▾Hide ▴
Rule
PM1 requires location in a mutational hotspot or critical functional domain without benign variation.
Evidence considered
  • No statistically significant hotspot identified for ZRSR2 R126
  • Hotspot review marked uncertain
Still missing
  • No curated germline domain-specific evidence was identified.
  • Hotspot review was marked uncertain and should be confirmed if PM1 is being considered.
Sources
hotspots ↗25586593
PM3 No data were identified showing this variant in trans with another pathogenic variant in an affected individual, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
PM3 requires detection in trans with a pathogenic variant for recessive disease.
Still missing
  • No phasing or second-allele data were provided.
PM6 No assumed de novo occurrence without confirmed parental testing was identified, so PM6 cannot be assessed. Details ▾Hide ▴
Rule
PM6 requires presumed de novo occurrence without full parental confirmation.
Still missing
  • Parental testing or de novo reporting was not provided.
PP1 No segregation data were identified, so PP1 cannot be applied. Details ▾Hide ▴
Rule
PP1 requires cosegregation with disease in multiple affected family members.
Still missing
  • Family segregation data were not provided.
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. Details ▾Hide ▴
Rule
PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology.
Still missing
  • Clinical phenotype and diagnostic specificity were not provided.
PP5 No reputable source classification for this specific variant was identified that could be considered under PP5, and the variant is absent from ClinVar. Details ▾Hide ▴
Rule
PP5 requires a reputable source reporting the variant as pathogenic without accessible primary evidence.
Evidence considered
  • ClinVar absent
Still missing
  • No germline expert or clinical laboratory assertion for this specific variant was identified.
Sources
clinvar ↗
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. Details ▾Hide ▴
Rule
BS2 requires observation in healthy adults for a fully penetrant dominant or relevant age-dependent condition.
Still missing
  • No healthy carrier data were identified.
BS3 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. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect for the specific variant.
Evidence considered
  • General ZRSR2 functional literature only
  • No benign functional evidence for p.(Arg126Ter)
Still missing
  • No variant-specific normal-function assay result was identified.
Sources
PMID:25586593 ↗literature_pass25586593
BS4 No family data were identified showing lack of segregation with disease, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
BS4 requires lack of segregation in affected family members.
Still missing
  • Family segregation data were not provided.
BP2 No phase information or second-variant data were identified to support BP2, so this criterion cannot be assessed. Details ▾Hide ▴
Rule
BP2 requires observation in trans with a pathogenic variant for a dominant disorder or in cis for any inheritance pattern.
Still missing
  • No cis/trans phasing data were provided.
BP3 No evidence was identified showing that this variant lies in a repetitive region without known function, so BP3 cannot be assessed. Details ▾Hide ▴
Rule
BP3 applies to in-frame indels in repetitive regions without known function.
Still missing
  • No repeat-region annotation was provided.
BP5 No alternate molecular diagnosis or alternate established cause for the phenotype was provided, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
BP5 requires a variant found in a case with an alternate molecular basis for disease.
Still missing
  • Clinical differential diagnosis information was not provided.
BP6 No reputable source classification reporting this variant as benign was identified, and the variant is absent from ClinVar. Details ▾Hide ▴
Rule
BP6 requires a reputable source reporting the variant as benign without accessible primary evidence.
Evidence considered
  • ClinVar absent
Still missing
  • No benign assertion from a reputable source was identified.
Sources
clinvar ↗
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 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. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously established pathogenic variant.
Evidence considered
  • Protein consequence: p.(Arg126Ter)
  • No ClinVar entry identified
Sources
prefetchclinvar ↗
PM4 N/APM4 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. Details ▾Hide ▴
Rule
PM4 does not apply to a standard premature stop codon already evaluated under PVS1.
Evidence considered
  • Variant bucket: nonsense
  • Protein consequence: p.(Arg126Ter)
Sources
prefetchpvs1_variant_assessment
PM5 N/APM5 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. Details ▾Hide ▴
Rule
PM5 is limited to missense variants.
Evidence considered
  • Protein consequence: nonsense p.(Arg126Ter)
Sources
prefetch
PP2 N/APP2 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. Details ▾Hide ▴
Rule
PP2 is limited to missense variants.
Evidence considered
  • Protein consequence: nonsense p.(Arg126Ter)
Sources
prefetch
PP3 N/ASpliceAI 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. Details ▾Hide ▴
Rule
PP3 was not applied because the available computational evidence does not provide independent support beyond the truncating consequence.
Evidence considered
  • SpliceAI max delta score 0.10
  • Variant consequence: nonsense p.(Arg126Ter)
Sources
spliceai ↗prefetch
BP1 N/ABP1 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. Details ▾Hide ▴
Rule
BP1 is limited to missense variants.
Evidence considered
  • Protein consequence: nonsense p.(Arg126Ter)
Sources
prefetch
BP4 N/ASpliceAI 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. Details ▾Hide ▴
Rule
BP4 was not applied because the computational prediction does not outweigh the established truncating consequence.
Evidence considered
  • SpliceAI max delta score 0.10
  • Variant consequence: nonsense p.(Arg126Ter)
Sources
spliceai ↗prefetch
BP7 N/ABP7 applies to synonymous variants or intronic variants with no predicted splice impact. This variant is a nonsense coding change, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 is limited to synonymous or certain noncoding variants.
Evidence considered
  • Protein consequence: nonsense p.(Arg126Ter)
  • SpliceAI max delta score 0.10
Sources
prefetchspliceai ↗

Identifiers

Gene
ZRSR2
Transcript
NM_005089.3
Coding (HGVS c.)
NM_005089.3:c.376C>T
Protein (HGVS p.)
NP_005080.1:p.(Arg126Ter)
GRCh38
chrX:15804174 C>T
GRCh37
chrX:15822297 C>T

Gene diagram

Every interpreted variant in ZRSR2, mapped onto the exon structure of NM_005089.3. Select a row to find it on the plot.

ZRSR2NM_005089.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ASpliceAI 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. Details ▾Hide ▴
Rule
PP3 was not applied because the available computational evidence does not provide independent support beyond the truncating consequence.
Evidence considered
  • SpliceAI max delta score 0.10
  • Variant consequence: nonsense p.(Arg126Ter)
Sources
spliceai ↗prefetch
BP4 N/ASpliceAI 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. Details ▾Hide ▴
Rule
BP4 was not applied because the computational prediction does not outweigh the established truncating consequence.
Evidence considered
  • SpliceAI max delta score 0.10
  • Variant consequence: nonsense p.(Arg126Ter)
Sources
spliceai ↗prefetch
BP7 N/ABP7 applies to synonymous variants or intronic variants with no predicted splice impact. This variant is a nonsense coding change, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 is limited to synonymous or certain noncoding variants.
Evidence considered
  • Protein consequence: nonsense p.(Arg126Ter)
  • SpliceAI max delta score 0.10
Sources
prefetchspliceai ↗

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

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

Functional

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

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.