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ZRSR2c.617T>CUncertain significance
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Variant interpretation report

ZRSR2 c.617T>C, p.(Phe206Ser)

NM_005089.3:c.617T>C NP_005080.1:p.(Phe206Ser) 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 gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the non-VCEP PM2 threshold of 0.1%. This supports rarity in the general population.

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.

SpliceAI score
0.090 maximum delta

Recorded SpliceAI maximum delta score: 0.090. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
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
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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 · 7 not met · 15 not assessed · 5 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.617T>C (p.Phe206Ser; p.F206S) variant has not been reported in ClinVar and does not lie in a statistically significant hotspot.

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

Available curated review did not identify variant-specific reviewed functional evidence for this variant.

In silico evidence is mixed: BayesDel is positive at 0.563308, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.09, so computational findings do not currently support PP3 or BP4.

Met · 1

PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the non-VCEP PM2 threshold of 0.1%. This supports rarity in the general population. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 7 · evaluated, threshold not reached

PS4 No enrichment of this variant in affected individuals was identified, and no unrelated case series or case-control data were found to support increased prevalence in affected individuals over controls. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • Variant absent from gnomAD v2.1 and v4.1 but no affected-case series identified
Still missing
  • No affected-case counts or case-control data were identified.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PM1 Available evidence does not support that residue 206 lies in a statistically significant hotspot or a well-established critical functional region without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this position. Details ▾Hide ▴
Evidence considered
  • No hotspot row identified for ZRSR2 F206
Still missing
  • No curated domain-specific pathogenic clustering evidence was identified for residue 206.
Sources
hotspots ↗
PP3 Computational evidence is insufficiently consistent to support PP3. BayesDel predicts a deleterious effect with a score of 0.563308, but SpliceAI predicts no significant splice impact with a maximum delta score of 0.09, and no REVEL score was available. Details ▾Hide ▴
Evidence considered
  • BayesDel score 0.563308
  • SpliceAI max delta score 0.09 predicts no significant splice impact
Still missing
  • No REVEL score was available.
  • Additional validated missense-specific computational evidence would be needed for stronger support.
Sources
bayesdelspliceai ↗
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the BA1 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 gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the BS1 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 ↗
BS2 This variant has not been observed in population databases, so occurrence in healthy individuals does not support BS2. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Still missing
  • No unaffected carrier data were identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 Computational evidence does not support BP4. SpliceAI predicts no significant splice impact with a maximum delta score of 0.09, but BayesDel is positive at 0.563308 for a deleterious missense effect, so the available in silico evidence is not uniformly benign. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.09
  • BayesDel score 0.563308
Still missing
  • No REVEL score was available.
  • Additional concordant benign computational evidence would be needed to support BP4.
Sources
spliceai ↗bayesdel

Not assessed · 15 · no assessment recorded

PS1 No established pathogenic or likely pathogenic variant causing the same amino acid change was identified, so PS1 was not assessed. Details ▾Hide ▴
Evidence considered
  • ClinVar search did not identify this variant
Still missing
  • A confirmed pathogenic or likely pathogenic same-amino-acid comparator was not identified.
Sources
clinvar ↗
PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 was not assessed. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission or publication evidence with de novo data was identified
Still missing
  • No trio-based or parental testing data were identified.
Sources
clinvar ↗
PS3 No well-established functional study demonstrating a damaging effect of this specific variant was identified, so PS3 was not assessed. Details ▾Hide ▴
Evidence considered
  • Curated review did not identify variant-specific reviewed functional evidence
Still missing
  • No variant-specific validated functional assay was identified.
Sources
oncokb ↗
PM3 No data were identified showing this variant in trans with a pathogenic variant in an affected individual, so PM3 was not assessed. Details ▾Hide ▴
Still missing
  • No phase or recessive-case data were identified.
PM6 No assumed de novo occurrence without parental confirmation was identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission or publication evidence with de novo-type data was identified
Still missing
  • No case report with limited parental data was identified.
Sources
clinvar ↗
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission or publication evidence with family segregation data was identified
Still missing
  • No pedigree or co-segregation data were identified.
Sources
clinvar ↗
PP2 Available evidence does not establish that missense variation is a common disease mechanism for ZRSR2, so PP2 was not assessed. Details ▾Hide ▴
Evidence considered
  • Generic review supports loss of function as a disease mechanism for ZRSR2
Still missing
  • A gene-specific missense mechanism framework was not available.
Sources
pvs1_gene_context
PP4 No phenotype-specific clinical evidence was provided to show a presentation highly specific for a ZRSR2-related disorder, so PP4 was not assessed. Details ▾Hide ▴
Still missing
  • No phenotype-to-gene specificity data were identified for the individual carrying this variant.
PP5 No reputable-source pathogenic classification without accessible supporting evidence was identified, so PP5 was not assessed. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • No external pathogenic classification source was identified for this variant.
Sources
clinvar ↗
BS3 No well-established functional study showing normal function for this specific variant was identified, so BS3 was not assessed. Details ▾Hide ▴
Evidence considered
  • Curated review did not identify variant-specific reviewed functional evidence
Still missing
  • No validated benign functional assay was identified.
Sources
oncokb ↗
BS4 No non-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Evidence considered
  • No ClinVar submission or publication evidence with non-segregation data was identified
Still missing
  • No family data showing lack of segregation with disease were identified.
Sources
clinvar ↗
BP1 Available evidence does not sufficiently establish that missense variants in ZRSR2 are generally less likely to be disease-causing than truncating variants, so BP1 was not assessed. Details ▾Hide ▴
Evidence considered
  • Generic review supports loss of function as a disease mechanism for ZRSR2
Still missing
  • A gene-specific missense-versus-truncating disease spectrum framework was not available.
Sources
pvs1_gene_context
BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant, so BP2 was not assessed. Details ▾Hide ▴
Still missing
  • No case-level phase information was identified.
BP5 No evidence was identified showing that an alternate molecular cause fully explains the observed phenotype, so BP5 was not assessed. Details ▾Hide ▴
Still missing
  • No alternate-cause clinical correlation data were provided.
BP6 No reputable-source benign classification without accessible supporting evidence was identified, so BP6 was not assessed. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • No external benign classification source was identified for this variant.
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.(Phe206Ser), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice variants. Although germline loss of function is a supported disease mechanism for ZRSR2, available evidence does not support applying PVS1 to this specific variant. Details ▾Hide ▴
Evidence considered
  • ZRSR2 loss of function is an eligible disease mechanism for generic PVS1 fallback
  • NM_005089.3:c.617T>C is a missense variant outside default PVS1 null-variant buckets
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMC6185798
PM4 N/AThis variant is a missense substitution and does not cause a protein length change, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Phe206Ser) missense
PM5 N/APM5 was not applied because no qualified same-residue pathogenic comparator was identified, and available review materials could not safely confirm classic same-residue PM5 semantics for this case. Details ▾Hide ▴
Evidence considered
  • PM5 candidate review found no same-residue comparator candidates and could not confirm classic PM5 use
Still missing
  • No expert-supported same-residue pathogenic comparator was identified.
Sources
pm5_candidates
BP3 N/AThis variant is not an in-frame deletion or insertion within a repetitive region, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Phe206Ser) missense
BP7 N/AThis variant is a missense substitution rather than a synonymous or intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Phe206Ser) missense

Identifiers

Gene
ZRSR2
Transcript
NM_005089.3
Coding (HGVS c.)
NM_005089.3:c.617T>C
Protein (HGVS p.)
NP_005080.1:p.(Phe206Ser)
GRCh38
chrX:15815736 T>C
GRCh37
chrX:15833859 T>C

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.

SpliceAI and Pangolin

SpliceAI acceptor lossat +23 bp
0.000
SpliceAI acceptor gainat -7 bp
0.090
SpliceAI donor lossat -115 bp
0.000
SpliceAI donor gainat +154 bp
0.030
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.050

Other predictors

REVEL
Not available
BayesDel
0.563

How the predictions were used

PP3 Computational evidence is insufficiently consistent to support PP3. BayesDel predicts a deleterious effect with a score of 0.563308, but SpliceAI predicts no significant splice impact with a maximum delta score of 0.09, and no REVEL score was available. Details ▾Hide ▴
Evidence considered
  • BayesDel score 0.563308
  • SpliceAI max delta score 0.09 predicts no significant splice impact
Still missing
  • No REVEL score was available.
  • Additional validated missense-specific computational evidence would be needed for stronger support.
Sources
bayesdelspliceai ↗
BP4 Computational evidence does not support BP4. SpliceAI predicts no significant splice impact with a maximum delta score of 0.09, but BayesDel is positive at 0.563308 for a deleterious missense effect, so the available in silico evidence is not uniformly benign. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.09
  • BayesDel score 0.563308
Still missing
  • No REVEL score was available.
  • Additional concordant benign computational evidence would be needed to support BP4.
Sources
spliceai ↗bayesdel
BP7 N/AThis variant is a missense substitution rather than a synonymous or intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Phe206Ser) missense

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). BayesDel score = 0.563308.

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 Recorded maximum delta 0.090 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 = 0.09). BayesDel score = 0.563308.

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.