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ZRSR2c.812A>GUncertain significance
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Variant interpretation report

ZRSR2 c.812A>G, p.(Tyr271Cys)

NM_005089.3:c.812A>G NP_005080.1:p.(Tyr271Cys) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

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: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.

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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ZRSR2, a splicing factor, is altered in various hematological malignancies.

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: 1 met · 5 not met · 18 not assessed · 4 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.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.

Met · 1

PM2 SupportingThis 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. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM2_Supporting for rarity
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 5 · evaluated, threshold not reached

PVS1 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. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 fallback via ClinGen SVI PVS1 recommendations
Evidence considered
  • Generic PVS1 eligibility for ZRSR2 was supported at the gene level.
  • Variant-level PVS1 scaffold classified this change as a non-null missense variant.
Still missing
  • Variant-specific RNA data were not identified to assess any cryptic splicing effect beyond the available in silico predictions.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMID:35371815 ↗PMID:38158857 ↗PMID:39761998 ↗PMID:25645650 ↗PMID:30977107 ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • ClinVar showed no entry for this variant.
Still missing
  • No affected-versus-control enrichment study for this exact variant was identified.
Sources
clinvar ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots did not identify a statistically significant hotspot for Y271 and flagged the review for human follow-up.
Still missing
  • Residue-level hotspot evidence remained uncertain and may benefit from manual review.
Sources
hotspots ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 18 · no assessment recorded

PS1 No evidence was identified that this amino acid change has a previously established pathogenic amino acid substitution at the same residue. Details ▾Hide ▴
Evidence considered
  • ClinVar showed no entry for this variant.
Still missing
  • No same-residue pathogenic comparison was identified in the reviewed sources.
Sources
clinvar ↗
PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar showed no entry for this variant.
Still missing
  • No family-based case report with confirmed maternity and paternity was identified.
Sources
clinvar ↗
PS3 No published well-established functional study was identified for p.Tyr271Cys (p.Y271C) showing a damaging effect. Details ▾Hide ▴
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence.
  • ClinVar showed no entry for this variant.
Still missing
  • No variant-specific functional assay results were identified.
Sources
oncokb ↗clinvar ↗
PM5 No evidence was identified that a different pathogenic missense change at codon 271 has been established. Details ▾Hide ▴
Evidence considered
  • ClinVar showed no entry for this variant.
Still missing
  • No pathogenic alternate missense change at the same residue was identified in the reviewed sources.
Sources
clinvar ↗
PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar showed no entry for this variant.
Still missing
  • No family-based report suggesting de novo occurrence was identified.
Sources
clinvar ↗
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar showed no entry for this variant.
Still missing
  • No pedigrees or family segregation studies were identified.
Sources
clinvar ↗
PP2 Available evidence does not establish a gene-specific missense-constraint pattern that would support PP2 for this variant. Details ▾Hide ▴
Evidence considered
  • No official or local gene-specific framework was retrieved.
Still missing
  • No validated gene-specific PP2 framework was available for ZRSR2 in this case.
Sources
final_classification_framework
PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.08.
  • BayesDel score 0.588005.
Still missing
  • REVEL was not available for this locus in the retrieved data.
  • Additional validated missense prediction evidence would help resolve computational interpretation.
Sources
spliceai ↗bayesdel
PP4 No phenotype-specific clinical evidence was provided to show a presentation highly specific for a single-gene ZRSR2 disorder. Details ▾Hide ▴
Still missing
  • Phenotype and inheritance details were not available for PP4 assessment.
PP5 No reputable source classification suitable for PP5 use was identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar showed no entry for this variant.
Still missing
  • ClinVar had no submission for this variant.
Sources
clinvar ↗
BS2 No evidence was identified showing this variant in healthy adult individuals in a manner sufficient to support BS2. Details ▾Hide ▴
Evidence considered
  • The variant was absent from gnomAD v2.1 and v4.1.
Still missing
  • No unaffected carrier observations were identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No published well-established functional study was identified for p.Tyr271Cys (p.Y271C) showing normal protein function or no damaging effect. Details ▾Hide ▴
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
  • No benign functional assay data were identified for this variant.
Sources
oncokb ↗
BS4 No family data were identified showing lack of segregation between this variant and disease. Details ▾Hide ▴
Evidence considered
  • ClinVar showed no entry for this variant.
Still missing
  • No non-segregation study was identified.
Sources
clinvar ↗
BP1 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. Details ▾Hide ▴
Evidence considered
  • ZRSR2 loss of function is supported at the gene level.
  • No official or local gene-specific framework was retrieved.
Still missing
  • No gene-specific missense versus truncating calibration was available for BP1 assessment.
Sources
pvs1_gene_contextfinal_classification_frameworkPMID:35371815 ↗PMID:38158857 ↗PMID:39761998 ↗PMID:25645650 ↗PMID:30977107 ↗
BP2 No phase information or second-variant context was identified to assess BP2. Details ▾Hide ▴
Still missing
  • No in trans or in cis observations with another variant were identified.
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.08.
  • BayesDel score 0.588005.
Still missing
  • REVEL was not available for this locus in the retrieved data.
  • Additional concordant benign missense prediction evidence would be needed for BP4.
Sources
spliceai ↗bayesdel
BP5 No alternate molecular diagnosis or other established cause of disease was provided to assess BP5. Details ▾Hide ▴
Still missing
  • Clinical correlation data were not available for BP5 assessment.
BP6 No reputable source reported this variant as benign or likely benign in the reviewed materials. Details ▾Hide ▴
Evidence considered
  • ClinVar showed no entry for this variant.
Still missing
  • ClinVar had no submission for this variant.
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is intended for recessive disorders with detected variants in trans, and that evidence context was not identified for this case. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length changes from in-frame insertions/deletions or stop-loss variants, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Variant consequence is p.Tyr271Cys (p.Y271C) missense.
BP3 N/ABP3 applies to in-frame insertions or deletions in repetitive regions without known function, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Variant consequence is p.Tyr271Cys (p.Y271C) missense.
BP7 N/ABP7 is intended for synonymous or certain noncoding variants with no predicted splice impact, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Variant consequence is missense
  • SpliceAI showed max delta 0.08 but BP7 does not apply to missense substitutions.
Sources
spliceai ↗

Identifiers

Gene
ZRSR2
Transcript
NM_005089.3
Coding (HGVS c.)
NM_005089.3:c.812A>G
Protein (HGVS p.)
NP_005080.1:p.(Tyr271Cys)
GRCh38
chrX:15818627 A>G
GRCh37
chrX:15836750 A>G

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 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.08.
  • BayesDel score 0.588005.
Still missing
  • REVEL was not available for this locus in the retrieved data.
  • Additional validated missense prediction evidence would help resolve computational interpretation.
Sources
spliceai ↗bayesdel
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.08.
  • BayesDel score 0.588005.
Still missing
  • REVEL was not available for this locus in the retrieved data.
  • Additional concordant benign missense prediction evidence would be needed for BP4.
Sources
spliceai ↗bayesdel
BP7 N/ABP7 is intended for synonymous or certain noncoding variants with no predicted splice impact, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Variant consequence is missense
  • SpliceAI showed max delta 0.08 but BP7 does not apply to missense substitutions.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). BayesDel score = 0.588005.

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 = 0.08). BayesDel score = 0.588005.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ZRSR2, a splicing factor, is altered in various hematological malignancies.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.