Variant classification summary

NM_000489.5:c.4699+2T>C

ATRX · NP_000480.3:p.? · NM_000489.5

GRCh37: chrX:76891404 A>G · GRCh38: chrX:77635913 A>G

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.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): canonical +2 donor splice-site disruption in intron 16 predicted to cause loss of function via nonsense-mediated decay (SpliceAI max delta 0.99).

2

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF 0, below the 0.1% threshold).

3

Combined, PVS1 + PM2 (one very strong plus one supporting) yields Likely Pathogenic under the SVI 2020 PM2-downgrade rule (posterior probability 0.988).

Final determination: Under the generic ACMG/AMP 2015 fallback rules (PMID:25741868, including the ClinGen SVI 2020 PM2-downgrade addendum), PVS1 (very strong) plus one supporting-strength criterion (PM2 at supporting strength) yields Likely Pathogenic (PVS1 + 1 supporting criterion = LP, Post_P 0.988); the combination does not meet any Pathogenic threshold (PVS1 + >=1 PS, >=2 PM, 1 PM + 1 PP, or >=2 PP) and no benign/likely-benign combination applies.

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 (Very Strong): disruption of the canonical +2 donor splice site of intron 16 is predicted to cause loss of function via nonsense-mediated decay (SpliceAI max delta 0.99).	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework spliceai gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PS1	N/A	Not applicable: no altered amino acid exists for this splice-site variant, so it cannot be compared with previously established pathogenic missense changes.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo occurrence is documented; no parental testing or parentage confirmation is available, and the variant is absent from ClinVar.	clinvar generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional assay evidence (RNA or protein studies) exists for this variant. Flagged for human review: RNA-based splicing studies of this +2 donor variant may exist in the literature and would strengthen the classification if found.	spliceai bayesdel generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no case-control, cohort, or proband reports of this variant exist in ClinVar or the literature.	clinvar generic_acmg_combination_rules
PM1	N/A	Not applicable: no altered amino acid residue exists for this splice-site variant, so hot-spot or critical-domain membership cannot be evaluated.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF 0, below the 0.1% PM2 threshold).	gnomad_v2 gnomad_v4 gnomad_canada pvs1_gene_context generic_acmg_combination_rules
PM3	N/A	Not applicable: ATRX is X-linked, so no second allele exists to be in trans; the variant also has zero observations anywhere.	generic_acmg_combination_rules clinvar gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	Not applicable: no in-frame indel or stop-loss change occurs; a splice-site variant produces no protein length change to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this position, so there is no same-residue pathogenic missense to compare against.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo observation of this variant is documented in any individual or source.	clinvar generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no pedigree or family genotyping data exist, so segregation with disease in affected relatives cannot be evaluated.	clinvar generic_acmg_combination_rules
PP2	N/A	Not applicable: no missense change is present, so the gene's missense-variant constraint properties are not relevant here.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI predicts near-certain splice disruption (max delta 0.99), but this same prediction already underlies PVS1 and is not double-counted.	spliceai bayesdel pvs1_variant_assessment pvs1_generic_framework generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family-history information is available, so phenotype specificity cannot be evaluated.	generic_acmg_combination_rules
PP5	Not met	Not met: no ClinVar record exists for this variant, so no expert-panel pathogenic classification is available.	clinvar
BA1	Not met	Not met: allele frequency is 0 across gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: allele frequency is 0 across gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >0.3% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with no hemizygous males or homozygous females observed.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional studies exist to show a lack of damaging effect, and the available in silico predictions (SpliceAI 0.99) point away from benign.	spliceai bayesdel generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no family genotyping or non-segregation data exist, so absence of segregation cannot be established.	clinvar generic_acmg_combination_rules
BP1	N/A	Not applicable: no missense change is present, so the gene's truncating-variant disease mechanism is not relevant to this splice variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase data exist to establish cis or trans arrangement, and the X-linked inheritance makes the trans prong inapplicable.	generic_acmg_combination_rules clinvar gnomad_v2 gnomad_v4 gnomad_canada
BP3	N/A	Not applicable: no in-frame indel occurs in a repetitive region; a splice-site variant produces no protein length change.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: all computational lines predict an impact (SpliceAI max delta 0.99), and no benign-direction prediction exists.	spliceai bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband molecular data exist, so an alternative genetic cause of disease cannot be evaluated.	generic_acmg_combination_rules
BP6	Not met	Not met: no ClinVar record exists for this variant, so no expert-panel benign classification is available.	clinvar
BP7	N/A	Not applicable: this is not a synonymous variant - the encoded protein sequence is altered at a canonical splice site.	generic_acmg_combination_rules

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