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
PVS1PM2
ATRX
c.5698-1G>C
p.?
This variant
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 applied · 18 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
NM_000489.5:c.5698-1G>C disrupts the canonical splice acceptor site (AG) at intron 23. ATRX loss of function is an established disease mechanism for ATR-X syndrome (MIM #301040) and associated cancer predisposition. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in genes with an established loss-of-function disease mechanism qualify for PVS1 at very strong strength. NM_000489.5 is the RefSeq select transcript, biologically relevant. The variant is absent from gnomAD, consistent with a pathogenic splice variant. PP3 is not stacked for the same splice-prediction evidence per PVS1 framework guidance.
Canonical splice acceptor site disrupted at intron 23 (c.5698-1G>CAG→AC)SpliceAI max delta score 0.86 (acceptor loss DS_AL=0.86
✓
PM2
moderate
Pathogenic
NM_000489.5:c.5698-1G>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Under the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868), complete absence from large population cohorts meets PM2 at moderate strength.
Absent from gnomAD v2.1 (0 alleles observed)Absent from gnomAD v4.1 (0 alleles observed)Absent from gnomAD-Canada v1.0 (0 alleles observed)
Assessed · not applied
· 18 not met · 0 not assessed
Pathogenic
PS2
No de novo observations have been reported for NM_000489.5:c.5698-1G>C in the literature or ClinVar.
PS3
No well-established functional studies (in vitro or in vivo) have been identified demonstrating a deleterious effect for NM_000489.5:c.5698-1G>C.
PS4
No case-control or cohort enrichment data are available for this variant.
PM1
This variant does not localize to a recognized mutational hotspot or critical functional domain within ATRX for which pathogenic enrichment has been established.
PM6
No de novo observations (with or without confirmed paternity) have been reported for NM_000489.5:c.5698-1G>C.
PP1
No co-segregation data are available for NM_000489.5:c.5698-1G>C in affected families.
PP3
SpliceAI predicts a deleterious effect on splicing (max delta 0.86, acceptor loss DS_AL=0.86).
PP4
No patient phenotype or detailed clinical data are available for independent assessment of phenotype specificity.
PP5
No reputable source (e.g., clinical diagnostic laboratory) has reported NM_000489.5:c.5698-1G>C as pathogenic.
Benign
BA1
NM_000489.5:c.5698-1G>C is absent from gnomAD v2.1 and v4.1 population databases.
BS1
NM_000489.5:c.5698-1G>C is absent from gnomAD v2.1 and v4.1 population databases.
BS2
No data are available regarding observation of NM_000489.5:c.5698-1G>C in healthy adults.
BS3
No well-established functional studies demonstrating no deleterious effect for NM_000489.5:c.5698-1G>C have been identified.
BS4
No segregation data are available to evaluate lack of segregation with disease for NM_000489.5:c.5698-1G>C.
BP2
No data are available regarding observation of NM_000489.5:c.5698-1G>C in trans with a known pathogenic ATRX variant.
BP4
Multiple lines of computational evidence predict a deleterious effect on splicing.
BP5
No alternative molecular basis for disease has been identified in an individual carrying NM_000489.5:c.5698-1G>C.
BP6
No reputable source has classified NM_000489.5:c.5698-1G>C as benign.
N/A · 5
PS1 · PM5 · PP2 · BP1 · BP7
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