NM_000489.5:c.3334A>G

ATRX · NP_000480.3:p.(Thr1112Ala) · NM_000489.5

GRCh37: chrX:76937414 T>C · GRCh38: chrX:77681922 T>C

Gene: ATRX Transcript: NM_000489.5

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

ATRX

Transcript

NM_000489.5

Protein

NP_000480.3:p.(Thr1112Ala)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	N/A	This 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.	pvs1_generic_framework
PS1	Not met	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.	clinvar
PS2	Not met	No de novo data are available for this variant. No publications report de novo occurrence, and no family-based sequencing data were identified.
PS3	Not met	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.	oncokb
PS4	Not met	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.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 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.	generic_acmg_combination_rules
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	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.	pm5_candidates clinvar
PM6	Not met	No de novo data are available. No publications report de novo occurrence of this variant, and no confirmatory parental testing data exist.
PP1	Not met	No co-segregation data are available. No family studies or pedigree data were identified in the evidence sources.
PP2	Not met	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.	pvs1_gene_context
PP3	Not met	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.	bayesdel spliceai
PP4	Not met	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.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.	bayesdel
BS4	Not met	No segregation data are available. BS4 requires lack of segregation with disease in affected family members; no family or pedigree data exist.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	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.
BP4	Met	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.	bayesdel spliceai
BP5	Not met	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.
BP6	Not met	The variant is absent from ClinVar. No reputable source has reported this variant as benign. BP6 requires a reputable source report; none exists.	clinvar
BP7	N/A	BP7 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).
BP3	N/A	Skipped per directive. BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
PM3	N/A	Skipped per directive. PM3 applies to recessive disorders with trans observation; ATRX is X-linked and this variant has no phasing data.
PM4	N/A	Skipped per directive. PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss; this is a missense substitution.

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