About ATRX
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATRX c.3334A>G, p.(Thr1112Ala)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold of <0.1% allele frequency in population databases for non-VCEP assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no damaging effect. BayesDel predicts a benign score of -0.527, and SpliceAI predicts no splicing impact (max delta score = 0.01). REVEL is not available. Two independent in silico tools support a benign interpretation.
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 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
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. ATRX, a tumor suppressor involved in transcriptional regulation, is infrequently altered in cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV64880047, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000489.5:c.3334A>G (p.Thr1112Ala) is a missense variant in ATRX, a chromatin remodeler gene associated with ATR-X syndrome and cancer predisposition. ATRX loss of function is an established germline disease mechanism.
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2). It is also absent from ClinVar.
Multiple in silico predictors suggest no damaging effect: BayesDel score is -0.527 (benign prediction) and SpliceAI predicts no splicing impact with a maximum delta score of 0.01 (BP4). REVEL score is not available.
The variant has been reported in COSMIC (COSV64880047) with two somatic occurrences. No variant-specific functional studies, de novo reports, segregation data, or case-control evidence were identified.
No functional data exist for this variant or a systematically characterized range that includes p.Thr1112. OncoKB classifies this variant as 'Unknown Oncogenic Effect.' No publications mention this exact variant.
Applying generic ACMG/AMP 2015 combination rules: met criteria include PM2 (moderate) and BP4 (supporting benign). The evidence is conflicting with limited overall weight. No pathogenic criteria beyond PM2 are met, and BP4 provides supporting benign evidence. The variant is best classified as a Variant of Uncertain Significance.
No criteria match.
Met · 2
PM2 ModerateThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold of <0.1% allele frequency in population databases for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada v1.0 (AF = 0.0).
Sources
BP4 SupportingMultiple lines of computational evidence suggest no damaging effect. BayesDel predicts a benign score of -0.527, and SpliceAI predicts no splicing impact (max delta score = 0.01). REVEL is not available. Two independent in silico tools support a benign interpretation. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.527 (benign prediction)
- SpliceAI max delta: 0.01 (no splice impact)
- REVEL: not found.
Sources
bayesdelspliceai ↗
Not met · 21 · evaluated, threshold not reached
PS1 No known pathogenic variant with the same amino acid change (p.Thr1112Ala) has been reported in ClinVar or the literature. The variant is absent from ClinVar and no publications describe a pathogenic missense change at this residue. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no same-amino-acid pathogenic comparator identified.
Sources
PS2 No de novo data are available for this variant. No publications report de novo occurrence, and no family-based sequencing data were identified. Details ▾Hide ▴
Evidence considered
- No de novo data across all evidence sources.
Still missing
- No trio or parental data available.
PS3 No functional data exist for this variant or a systematically characterized range that includes p.Thr1112. OncoKB classifies this variant as 'Unknown Oncogenic Effect' and no publications with variant-specific functional assays were identified. COSMIC reports two somatic occurrences, but somatic count alone does not constitute functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- COSMIC COSV64880047 with n=2 somatic occurrences
- no functional assays in literature.
Still missing
- No experimental functional characterization of p.Thr1112Ala.
Sources
PS4 No case-control or prevalence data are available. The variant is absent from population databases but there are no affected case counts or statistical enrichment data to meet PS4 thresholds. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
- but no case cohort data for comparison.
Still missing
- No case-control or cohort enrichment data.
Sources
PM1 The variant does not lie within a statistically significant mutational hotspot (cancerhotspots.org) and no functional domain characterization specifically identifying residue 1112 as critical was identified in the available evidence. ATRX has known functional domains (ADD, SNF2 helicase) but p.Thr1112 is not within a well-characterized domain hotspot in the provided evidence. Details ▾Hide ▴
Evidence considered
- Not in a statistically significant hotspot per cancerhotspots.org
- no domain-level functional characterization for residue 1112 in evidence.
Still missing
- Domain-level residue characterization for p.Thr1112 not available.
PM5 No same-residue pathogenic comparator variant was identified. ClinVar contains no entries at p.Thr1112 with a different pathogenic missense change, and automated PM5 candidate harvesting found zero candidates. Details ▾Hide ▴
Evidence considered
- Zero same-residue ClinVar candidates
- PM5 candidate harvesting returned no results.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo data are available. No publications report de novo occurrence of this variant, and no confirmatory parental testing data exist. Details ▾Hide ▴
Evidence considered
- No de novo reports in literature or evidence sources.
Still missing
- No trio or parental testing data.
PP1 No co-segregation data are available. No family studies or pedigree data were identified in the evidence sources. Details ▾Hide ▴
Evidence considered
- No family or co-segregation data.
Still missing
- No pedigree or segregation analysis.
PP2 While ATRX loss of function is an established disease mechanism (ATR-X syndrome), the gene-level missense constraint data (e.g., missense Z-score) are not available in the evidence. PP2 requires both a low rate of benign missense variation and missense variants as a common disease mechanism; insufficient data to satisfy this criterion. Details ▾Hide ▴
Evidence considered
- ATRX LOF mechanism supported for disease
- but missense constraint metrics not provided
- PP2 cannot be confidently applied.
Still missing
- No missense constraint metrics (Z-score
- gnomAD constraint) in evidence.
Sources
pvs1_gene_context
PP3 Multiple in silico tools do not support a deleterious effect. BayesDel score is -0.527 (predicts benign). REVEL score is not available. SpliceAI predicts no splicing impact (max delta 0.01). No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.527 (benign)
- SpliceAI max delta: 0.01 (no splice impact)
- REVEL not found.
Sources
bayesdelspliceai ↗
PP4 No patient phenotype or clinical data were provided. PP4 requires a phenotype or family history highly specific for the gene/disease; absent patient data precludes assessment. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available.
Still missing
- No clinical phenotype information provided.
PP5 The variant is absent from ClinVar. No reputable source (expert panel, clinical laboratory) has reported this variant as pathogenic. PP5 requires a reputable source report; none exists for this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source reports it as pathogenic.
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0, well below the BA1 threshold of >1% for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
- AF = 0.0 across all gnomAD datasets
- far below BA1 threshold of 1%.
Sources
BS1 The variant is absent from gnomAD v2.1 and v4.1. The allele frequency is 0.0, below the BS1 threshold of >0.3% for non-VCEP assessment. Absence from population databases is consistent with PM2, not BS1. Details ▾Hide ▴
Evidence considered
- AF = 0.0 in gnomAD
- does not meet BS1 threshold (>0.3%).
Sources
BS2 No evidence of observation in healthy adults. The variant is absent from all population databases, and no specific reports of healthy individuals carrying this variant were identified. BS2 requires observation in a healthy adult; this is not met. Details ▾Hide ▴
Evidence considered
- Variant absent from population databases
- no healthy adult carriers identified.
Sources
BS3 No functional studies demonstrating no damaging effect are available. While BayesDel predicts a benign score (-0.527), in silico prediction alone does not satisfy BS3, which requires experimental functional evidence. No publications with variant-specific functional assays were identified. Details ▾Hide ▴
Evidence considered
- BayesDel predicts benign (-0.527) but no experimental functional studies demonstrating no damaging effect.
Still missing
- No in vitro or in vivo functional studies for this variant.
Sources
bayesdel
BS4 No segregation data are available. BS4 requires lack of segregation with disease in affected family members; no family or pedigree data exist. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No pedigree or segregation analysis.
BP1 ATRX missense variants are reported in association with ATR-X syndrome and cancer predisposition. The disease mechanism includes loss of function from missense variants, not exclusively truncating variants. BP1 is not applicable because missense variants are a known disease mechanism in ATRX. Details ▾Hide ▴
Evidence considered
- ATRX disease mechanism includes missense variants
- BP1 (truncating-only criterion) does not apply.
Sources
pvs1_gene_context
BP2 No phasing data are available. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant; no such data exist. Details ▾Hide ▴
Evidence considered
- No phasing or allelic data available.
Still missing
- No variant phasing information.
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease. BP5 requires observation in a case with a clear alternate cause; no such data exist. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause data available.
Still missing
- No data on cases with alternate molecular diagnoses.
BP6 The variant is absent from ClinVar. No reputable source has reported this variant as benign. BP6 requires a reputable source report; none exists. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source reports it as benign.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Thr1112Ala), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 Decision Tree (PMC6185798), the variant falls into the 'other' bucket and does not meet criteria for PVS1 application. Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant bucket = other
- apply_generic_pvs1_framework = false per PVS1 variant assessment scaffold.
Sources
PM3 N/ASkipped per directive. PM3 applies to recessive disorders with trans observation; ATRX is X-linked and this variant has no phasing data. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per directive. PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASkipped per directive. BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies only to synonymous variants where splicing prediction algorithms predict no impact on the splice consensus sequence or a new splice site. This is a missense variant (p.Thr1112Ala). Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous variants.
PS5 N/APS5 is not defined in the standard ACMG/AMP 2015 classification framework (Richards et al. 2015, PMID:25741868), which is the governing framework for this case (generic_acmg fallback). This criterion is not available for adjudication. Details ▾Hide ▴
Evidence considered
- PS5 is not a standard ACMG/AMP 2015 criterion.
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- ATRX
- Transcript
- NM_000489.5
- Coding (HGVS c.)
- NM_000489.5:c.3334A>G
- Protein (HGVS p.)
- NP_000480.3:p.(Thr1112Ala)
- GRCh38
- chrX:77681922 T>C
- GRCh37
- chrX:76937414 T>C
- COSMIC
- COSV64880047
Gene diagram
Every interpreted variant in ATRX, mapped onto the exon structure of NM_000489.5. Select a row to find it on the plot.
ATRXNM_000489.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ATRX
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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
Other predictors
- REVEL
- Not available
- BayesDel
- -0.527
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no damaging effect. BayesDel predicts a benign score of -0.527, and SpliceAI predicts no splicing impact (max delta score = 0.01). REVEL is not available. Two independent in silico tools support a benign interpretation. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.527 (benign prediction)
- SpliceAI max delta: 0.01 (no splice impact)
- REVEL: not found.
Sources
bayesdelspliceai ↗
PP3 Multiple in silico tools do not support a deleterious effect. BayesDel score is -0.527 (predicts benign). REVEL score is not available. SpliceAI predicts no splicing impact (max delta 0.01). No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.527 (benign)
- SpliceAI max delta: 0.01 (no splice impact)
- REVEL not found.
Sources
bayesdelspliceai ↗
BP7 N/ABP7 applies only to synonymous variants where splicing prediction algorithms predict no impact on the splice consensus sequence or a new splice site. This is a missense variant (p.Thr1112Ala). 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 = 0.01). BayesDel score = -0.526868.
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 0.010
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000489.5%3Ac.3334A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-76937414-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-77681922-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/X-77681922-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000489.5%3Ac.3334…
- OncoKB ↗www.oncokb.org/gene/ATRX/T1112A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=140427750
- Cancer hotspots ↗www.cancerhotspots.org/
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 = 0.01). BayesDel score = -0.526868.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATRX, a tumor suppressor involved in transcriptional regulation, is infrequently altered in cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64880047, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.