Variant classification summary

NM_000489.5:c.4231G>T

ATRX · NP_000480.3:p.(Glu1411Ter) · NM_000489.5

GRCh37: chrX:76909674 C>A · GRCh38: chrX:77654184 C>A

Gene: ATRX Transcript: NM_000489.5

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

ATRX

Transcript

NM_000489.5

Protein

NP_000480.3:p.(Glu1411Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PVS1 very strong reflects the predicted NMD-sensitive ATRX truncation.

2

Likely Pathogenic: PM2 supporting reflects absence from gnomAD v2.1 and v4.1.

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong pathogenic criterion plus one supporting pathogenic criterion supports a Likely Pathogenic classification.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Met: ATRX nonsense variant p.Glu1411Ter in exon 14 truncates the 2493-amino-acid protein to 1411 residues and is predicted to undergo NMD.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000489.5:c.4231G>T in ATRX is a nonsense substitution introducing a premature stop codon predicted to produce NP_000480.3:p.(Glu1411Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no affected-proband phenotype or parental genotype results establish that NM_000489.5:c.4231G>T arose de novo.
PS3	Not assessed	Not assessed: no reviewed study experimentally tested ATRX c.4231G>T (p.Glu1411Ter) in a validated functional assay.
PS4	Not assessed	Not assessed: no affected-case/control counts or statistically supported enrichment estimate are available for this exact variant.
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000489.5:c.4231G>T in ATRX is a nonsense substitution introducing a premature stop codon predicted to produce NP_000480.3:p.(Glu1411Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	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 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband or phase data document a second pathogenic ATRX variant in trans for this X-linked condition.
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000489.5:c.4231G>T in ATRX is a nonsense substitution introducing a premature stop codon predicted to produce NP_000480.3:p.(Glu1411Ter). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000489.5:c.4231G>T in ATRX is a nonsense substitution introducing a premature stop codon predicted to produce NP_000480.3:p.(Glu1411Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no presumed-de-novo observation with documented phenotype, parental testing, relationship confirmation, or independent case count is available.
PP1	Not assessed	Not assessed: no affected relatives, unaffected relatives, genotypes, informative meioses, or independent families are reported for segregation analysis.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000489.5:c.4231G>T in ATRX is a nonsense substitution introducing a premature stop codon predicted to produce NP_000480.3:p.(Glu1411Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: NM_000489.5:c.4231G>T is a nonsense variant, outside PP3's missense or splice-region/intronic scope.
PP4	Not assessed	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	Not met: ClinVar has no exact-variant record, so no expert-panel Pathogenic or Likely pathogenic assertion supports PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the generic BA1 allele-frequency threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show absence, with no observed allele frequency reaching the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 report no observed carriers, so no healthy homozygote or hemizygote observation supports BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no reviewed study tested ATRX c.4231G>T (p.Glu1411Ter) and demonstrated a normal functional result.
BS4	Not assessed	Not assessed: no tested relatives with discordant variant and disease status are documented to demonstrate non-segregation.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000489.5:c.4231G>T in ATRX is a nonsense substitution introducing a premature stop codon predicted to produce NP_000480.3:p.(Glu1411Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase or inheritance data show this ATRX variant in trans or cis with another pathogenic variant.
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000489.5:c.4231G>T in ATRX is a nonsense substitution introducing a premature stop codon predicted to produce NP_000480.3:p.(Glu1411Ter). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: NM_000489.5:c.4231G>T is a nonsense variant, outside BP4's missense or splice-region/intronic scope.
BP5	Not assessed	Not assessed: no case-level alternative molecular diagnosis is documented that could independently explain the patient's phenotype.
BP6	Not met	Not met: ClinVar has no exact-variant record, so no expert-panel Benign or Likely benign assertion supports BP6.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000489.5:c.4231G>T in ATRX is a nonsense substitution introducing a premature stop codon predicted to produce NP_000480.3:p.(Glu1411Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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