PVS1 is met at very strong strength: NM_000489.5:c.5698-1G>C disrupts the canonical splice acceptor site at intron 23. ATRX loss of function is an established disease mechanism for ATR-X syndrome. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in LOF-established genes receive PVS1 at very strong strength.1 PM2 is met at moderate strength: this variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Complete absence from large population cohorts meets PM2 at moderate strength under generic ACMG/AMP 2015.2 No benign criteria are met. Computational evidence (SpliceAI max delta 0.86, BayesDel 0.83) predicts a deleterious splicing effect, consistent with the PVS1 determination. PP3 is not applied independently per PVS1 framework guidance against double-counting splice prediction evidence.3 Overall classification: Likely Pathogenic. The combination of PVS1 (very strong) and PM2 (moderate) meets the Likely Pathogenic threshold under generic ACMG/AMP 2015 combination rules (1 Very Strong + 1 Moderate).4
ATRX
Final classification
Likely Pathogenic
ATRX c.5698-1G>C · p.?
ATRX
PVS1 is met at very strong strength: NM_000489.5:c.5698-1G>C disrupts the canonical splice acceptor site at intron 23. ATRX loss of function is an established disease mechanism for ATR-X syndrome. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in LOF-established genes receive PVS1 at very strong strength.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
ATRX c.5698-1G>C
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessmentspliceai ↗
3
spliceai ↗bayesdelpvs1_variant_assessment
4
generic_acmg_combination_rules
Gene diagram
· NM_000489.5 · variants mapped to exon structure
ATRX
NM_000489.5
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.86). BayesDel score = 0.83.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV64881768, n = 2 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links