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ZRSR2c.758T>CUncertain significance
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Variant interpretation report

ZRSR2 c.758T>C, p.(Val253Ala)

NM_005089.3:c.758T>C NP_005080.1:p.(Val253Ala) 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

NM_005089.3:c.758T>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). The variant allele frequency is well below the 0.1% threshold for PM2 application in a gene without a CSPEC-specific frequency cutoff.

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
0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. 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.

29 criteria with recorded statuses: 1 met · 21 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_005089.3:c.758T>C (p.Val253Ala) is a missense variant in ZRSR2, a gene encoding a component of the minor spliceosome that is implicated in myelodysplastic syndromes, spliceosomopathies, and oral-facial-digital syndrome.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting level.

The variant is absent from ClinVar, COSMIC, and CancerHotspots.org; no variant-specific functional data, segregation data, or de novo observations are available.

SpliceAI predicts no significant splicing impact (max delta score 0.04). BayesDel add score is 0.527 (above the 0.27 damaging threshold), but as the sole predictor available, it does not meet the PP3 multiple-lines requirement.

No publications in the literature packet mention the specific variant NM_005089.3:c.758T>C (p.Val253Ala). Five PMIDs reviewed for ZRSR2 gene-level context did not contain variant-specific data.

PVS1 is not applicable as this is a missense variant not falling into the null-variant buckets of the ClinGen PVS1 decision framework (PMC6185798).

Overall classification is limited by paucity of evidence. Only one supporting-level criterion (PM2) is met, which is insufficient to reach a Likely Pathogenic or Pathogenic classification under generic ACMG/AMP 2015 combination rules. No benign criteria are met.

Met · 1

PM2 SupportingNM_005089.3:c.758T>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). The variant allele frequency is well below the 0.1% threshold for PM2 application in a gene without a CSPEC-specific frequency cutoff. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes).
  • Absent from gnomAD-Canada v1.0 (HostSeq genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 21 · evaluated, threshold not reached

PS2 No de novo confirmation data are available for this variant. PS2 requires a de novo observation with both maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in literature or ClinVar.
Still missing
  • No sequencing of parental samples available.
PS3 No variant-specific functional data exist for NM_005089.3:c.758T>C (p.Val253Ala). OncoKB classifies this alteration as Unknown Oncogenic Effect with no curated functional evidence. No publications with functional characterization of this variant were identified. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional studies of this variant in literature.
Still missing
  • No in vitro or in vivo functional data for p.Val253Ala.
Sources
oncokb ↗
PS4 No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls are available. Details ▾Hide ▴
Evidence considered
  • No case-control or cohort enrichment data identified.
Still missing
  • No prevalence data in affected populations.
PM1 Residue 253 does not lie in a statistically significant cancer hotspot per CancerHotspots.org. No published functional domain characterization confirms that position 253 resides within a well-defined critical functional domain. The ZRSR2 zinc finger domains are located N-terminal to this position, and without specific domain boundary evidence encompassing residue 253, PM1 cannot be applied. Details ▾Hide ▴
Evidence considered
  • CancerHotspots.org: residue 253 not in a significant hotspot
  • no domain-level functional characterization available.
Still missing
  • No published functional domain boundaries encompassing residue 253.
PM6 No de novo observation reported for this variant. PM6 requires a de novo observation without confirmation of paternity and maternity. Details ▾Hide ▴
Evidence considered
  • No de novo data identified.
Still missing
  • No de novo reports available.
PP1 No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No multigenerational pedigree or segregation analysis.
PP2 ZRSR2 does not have an HCI prior score or externally calculated missense constraint metric available. Without evidence that ZRSR2 has a low rate of benign missense variation (z-score or equivalent), PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
  • No HCI prior or missense constraint metric available for ZRSR2.
Still missing
  • No gene-level missense constraint data
  • HCI prior not supported.
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no significant splicing impact (max delta score 0.04). BayesDel add score is 0.527, which is above the 0.27 damaging threshold, but this is the sole computational predictor available; REVEL was not found for this variant. A single computational line does not meet the PP3 multiple-lines requirement. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta 0.04 (no predicted splicing impact).
  • BayesDel: add score 0.527 (above damaging threshold of 0.27).
  • REVEL: not found for this variant.
Still missing
  • Only one damaging in silico predictor available
  • need additional computational lines for PP3.
Sources
spliceai ↗bayesdel
PP4 No patient phenotype or family history data are available for adjudication. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data available.
Still missing
  • Patient phenotype not provided for review.
PP5 This variant is absent from ClinVar. PP5 requires a reputable source (ClinVar 3-star expert panel or higher) to have classified the variant as pathogenic. No ClinVar entry exists for NM_005089.3:c.758T>C. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no PP5-qualifying classification available.
Sources
clinvar ↗
BA1 The variant is absent from all gnomAD datasets. Allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD allele frequency = 0% (absent)
  • does not meet >1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from all gnomAD datasets. Allele frequency is 0%, well below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD allele frequency = 0% (absent)
  • does not meet >0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observation of this variant in healthy adult controls beyond population databases is available. BS2 requires observation in a healthy adult individual for a fully penetrant disorder, or absence of phenotype specificity data. Details ▾Hide ▴
Evidence considered
  • No observation in healthy adult controls identified.
Still missing
  • No healthy control observations available.
BS3 No well-established in vitro or in vivo functional studies demonstrate a benign effect for this variant. No functional data of any kind were identified for p.Val253Ala. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no benign functional data identified.
Still missing
  • No functional studies demonstrating no damaging effect.
Sources
oncokb ↗
BS4 No family segregation or linkage data are available to demonstrate lack of segregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies available.
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. ZRSR2 germline disease has been associated with variation broadly (PMID:38158857 links ZRSR2 variation, not exclusively truncating, to oral-facial-digital syndrome). There is insufficient evidence that ZRSR2-associated disease is primarily caused by truncating variants alone. Details ▾Hide ▴
Evidence considered
  • ZRSR2 germline disease is not established as exclusively truncating-mediated
  • missense variation also reported in disease context.
Still missing
  • Insufficient evidence for a truncating-only disease mechanism.
Sources
pvs1_gene_context
BP2 BP2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in a recessive disorder. No such observations are available. Details ▾Hide ▴
Evidence considered
  • No observations in trans or cis with pathogenic variants.
Still missing
  • No phase data available.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. SpliceAI max delta score is 0.04 (no predicted splicing impact), but BayesDel add score is 0.527, which is above the damaging threshold. The in silico evidence is conflicted and does not meet the BP4 multiple-lines requirement for a benign computational consensus. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta 0.04 (no predicted splicing impact).
  • BayesDel: add score 0.527 (above damaging threshold of 0.27).
  • Computational evidence is conflicted
  • BP4 multiple-lines benign consensus not met.
Sources
spliceai ↗bayesdel
BP5 No observation of this variant in a case with an alternate molecular basis for disease is available. BP5 requires that the variant be found in an individual with a clear alternate genetic cause of their phenotype. Details ▾Hide ▴
Evidence considered
  • No case with alternate molecular etiology identified.
Still missing
  • No alternate-molecular-basis data available.
BP6 This variant is absent from ClinVar. BP6 requires a reputable source to have classified the variant as benign. No ClinVar entry exists for NM_005089.3:c.758T>C. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no BP6-qualifying benign classification available.
Sources
clinvar ↗
PS5 No established pathogenic variant with the same amino acid change (p.Val253Ala) from a different nucleotide change is recorded in ClinVar. PS5 requires a previously established pathogenic variant at the same residue regardless of nucleotide change. Details ▾Hide ▴
Evidence considered
  • No pathogenic variant identified at residue 253 in ClinVar.
Still missing
  • No same-residue comparator variants in ClinVar.
Sources
clinvar ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_005089.3:c.758T>C is a missense variant (p.Val253Ala). It does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The generic PVS1 decision framework (PMC6185798) was not triggered. Details ▾Hide ▴
Evidence considered
  • Missense substitution does not meet PVS1 null-variant criteria.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo ClinVar entry exists for this variant or any variant at this residue; no comparator nucleotide change yielding the same amino acid change is available. PS1 requires a known pathogenic variant with the same amino acid change but different nucleotide change. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no comparator nucleotide change identified.
Still missing
  • No ClinVar data available for same-residue comparators.
Sources
clinvar ↗
PM3 N/APM3 applies to recessive disorders with biallelic observations. No biallelic data or established recessive inheritance for ZRSR2 is available. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein-length changes from in-frame deletions/insertions or stop-loss variants. This is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue comparator variants with a pathogenic classification were identified in ClinVar. The automated PM5 candidate search returned zero candidates. Details ▾Hide ▴
Evidence considered
  • No pathogenic same-residue comparator variants found.
Sources
pm5_candidatesclinvar ↗
BP3 N/AThis is a substitution variant, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) variants. NM_005089.3:c.758T>C is a missense variant (p.Val253Ala), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is restricted to synonymous variants.

Identifiers

Gene
ZRSR2
Transcript
NM_005089.3
Coding (HGVS c.)
NM_005089.3:c.758T>C
Protein (HGVS p.)
NP_005080.1:p.(Val253Ala)
GRCh38
chrX:15815877 T>C
GRCh37
chrX:15834000 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
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +13 bp
0.000
SpliceAI acceptor gainat -148 bp
0.040
SpliceAI donor lossat -11 bp
0.000
SpliceAI donor gainat +13 bp
0.030
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.020

Other predictors

REVEL
Not available
BayesDel
0.527

How the predictions were used

PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no significant splicing impact (max delta score 0.04). BayesDel add score is 0.527, which is above the 0.27 damaging threshold, but this is the sole computational predictor available; REVEL was not found for this variant. A single computational line does not meet the PP3 multiple-lines requirement. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta 0.04 (no predicted splicing impact).
  • BayesDel: add score 0.527 (above damaging threshold of 0.27).
  • REVEL: not found for this variant.
Still missing
  • Only one damaging in silico predictor available
  • need additional computational lines for PP3.
Sources
spliceai ↗bayesdel
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. SpliceAI max delta score is 0.04 (no predicted splicing impact), but BayesDel add score is 0.527, which is above the damaging threshold. The in silico evidence is conflicted and does not meet the BP4 multiple-lines requirement for a benign computational consensus. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta 0.04 (no predicted splicing impact).
  • BayesDel: add score 0.527 (above damaging threshold of 0.27).
  • Computational evidence is conflicted
  • BP4 multiple-lines benign consensus not met.
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous (silent) variants. NM_005089.3:c.758T>C is a missense variant (p.Val253Ala), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is restricted to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.527207.

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 0.040 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.527207.

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.