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NM_000489.5:c.4231G>T
p.Glu1411Ter · ATRX
ACMG/AMP
0%
complete
Final classification
Likely Pathogenic
PVS1PM2
ATRX
c.4231G>T
p.Glu1411Ter
nonsense · exon 14
Gene context NCBI Gene ↗ OncoKB ↗

ATRX encodes a chromatin-remodeling protein in the SWI/SNF family that regulates gene expression, DNA methylation, and chromosome structure, including the incorporation of histone H3.3 during telomere replication. Germline mutations in ATRX cause an X-linked syndrome characterized by intellectual disability and alpha-thalassemia. In cancer, ATRX acts as a tumor suppressor: its loss promotes an alternative lengthening of telomeres (ALT) pathway, chromosomal instability, and epigenetic remodeling in a variety of tumors, and tumors with ATRX mutations may be more sensitive to agents that target DNA repair.

This variant

This ATRX variant affects a gene whose loss of function causes an X-linked intellectual-disability and alpha-thalassemia syndrome, while ATRX loss also contributes to tumor-suppressor deficiency and alternative lengthening of telomeres in cancer.

Transcript
NM_000489.5
HGVS · transcript:coding
NM_000489.5:c.4231G>T
GRCh38
chrX:77654184 C>A
GRCh37
chrX:76909674 C>A
Likely Pathogenic: PVS1 (very strong) plus PM2 (supporting) meet the generic ACMG/AMP fallback combination rule.
Classification rationale
PVS1PM2 Likely Pathogenic
ATRX c.4231G>T nonsense · exon 14

Likely Pathogenic: PVS1 very strong reflects the predicted NMD-sensitive ATRX truncation. Likely Pathogenic: PM2 supporting reflects absence from gnomAD v2.1 and v4.1.

PVS1 + PM2 → Likely Pathogenic
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.
Gene diagram · NM_000489.5 · variants mapped to exon structure
ATRX NM_000489.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 16 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
PVS1 very strong Pathogenic
Met: ATRX nonsense variant p.Glu1411Ter in exon 14 truncates the 2493-amino-acid protein to 1411 residues and is predicted to undergo NMD.
The governing generic ClinGen SVI PVS1 framework is PMC6185798; its NMD rule predicts decay when a premature termination codon is not in the 3-prime-most exon or the 3-prime-most 50 bases of the penultimate exon.VariantValidator identifies NM_000489.5 as the RefSeq-selected ATRX transcript, places NM_000489.5:c.4231G>T in exon 14, and predicts NP_000480.3:p.(Glu1411Ter).The normalized protein annotation gives a full length of 2493 amino acids and a predicted truncated length of 1411 amino acids; the variant therefore removes the downstream C-terminal sequence.
pvs1_generic_framework ↗
PM2 supporting Pathogenic
Met at supporting strength: the variant is absent in gnomAD v2.1 and v4.1, observed frequency 0 versus the generic PM2 threshold of <=0.0001.
gnomAD v2.1 reports the variant as absent, corresponding to observed allele frequency 0 in that dataset.gnomAD v4.1 reports the variant as absent, corresponding to observed allele frequency 0 in that dataset.The supplied generic PM2 threshold is allele frequency <=0.0001 at supporting strength; both queried datasets meet this criterion.
gnomad_v2 ↗gnomad_v4 ↗
Assessed · not applied · 5 not met · 11 not assessed
Pathogenic
PS2 Not assessed: no affected-proband phenotype or parental genotype results establish that NM_000489.5:c.4231G>T arose de novo.
PS3 Not assessed: no reviewed study experimentally tested ATRX c.4231G>T (p.Glu1411Ter) in a validated functional assay.
PS4 Not assessed: no affected-case/control counts or statistically supported enrichment estimate are available for this exact variant.
PM3 Not assessed: no affected-proband or phase data document a second pathogenic ATRX variant in trans for this X-linked condition.
PM6 Not assessed: no presumed-de-novo observation with documented phenotype, parental testing, relationship confirmation, or independent case count is available.
PP1 Not assessed: no affected relatives, unaffected relatives, genotypes, informative meioses, or independent families are reported for segregation analysis.
PP4 Not assessed: no patient phenotype or disease-specificity assessment is available to evaluate whether the presentation is highly specific for ATRX-related disease.
PP5 Not met: ClinVar has no exact-variant record, so no expert-panel Pathogenic or Likely pathogenic assertion supports PP5.
Benign
BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the generic BA1 allele-frequency threshold of >=0.05.
BS1 Not met: gnomAD v2.1 and v4.1 show absence, with no observed allele frequency reaching the generic BS1 threshold of >=0.01.
BS2 Not met: gnomAD v2.1 and v4.1 report no observed carriers, so no healthy homozygote or hemizygote observation supports BS2.
BS3 Not assessed: no reviewed study tested ATRX c.4231G>T (p.Glu1411Ter) and demonstrated a normal functional result.
BS4 Not assessed: no tested relatives with discordant variant and disease status are documented to demonstrate non-segregation.
BP2 Not assessed: no phase or inheritance data show this ATRX variant in trans or cis with another pathogenic variant.
BP5 Not assessed: no case-level alternative molecular diagnosis is documented that could independently explain the patient's phenotype.
BP6 Not met: ClinVar has no exact-variant record, so no expert-panel Benign or Likely benign assertion supports BP6.
N/A · 10 PS1 · PM1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.83.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 5 PMIDs not cited in assessment
14592816 ↗ Acquired somatic ATRX mutations in myelodysplastic syndrome associated with alpha thalassemia (ATMDS) convey a more severe hematologic phenotype than germline ATRX mutations. ONCOKB
15591283 ↗ Attenuation of an amino-terminal premature stop codon mutation in the ATRX gene by an alternative mode of translational initiation. ONCOKB
17609377 ↗ Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX. ONCOKB
18409179 ↗ Mutations in the chromatin-associated protein ATRX. ONCOKB
21719641 ↗ Altered telomeres in tumors with ATRX and DAXX mutations. ONCOKB