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ATRX
Final classification
Likely Pathogenic
ATRX c.4699+2T>C · p.?
ATRX

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).

Gene
ATRX
Transcript
NM_000489.5
HGVS · transcript:coding
NM_000489.5:c.4699+2T>C
Consequence
N/A
GRCh38
chrX:77635913 A>G
GRCh37
chrX:76891404 A>G
Basis Likely Pathogenic: one very strong (PVS1) plus one supporting (PM2) criterion maps to Likely Pathogenic, posterior probability 0.988, under the SVI 2020 PM2-downgrade combination rule. ▾
Likely Pathogenic: one very strong (PVS1) plus one supporting (PM2) criterion maps to Likely Pathogenic, posterior probability 0.988, under the SVI 2020 PM2-downgrade combination rule.
Classification rationale
PVS1PM2 Likely Pathogenic
ATRX c.4699+2T>C

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). PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF 0, below the 0.1% threshold). Combined, PVS1 + PM2 (one very strong plus one supporting) yields Likely Pathogenic under the SVI 2020 PM2-downgrade rule (posterior probability 0.988).

PVS1 + PM2 → Likely Pathogenic
Gene diagram · NM_000489.5 · variants mapped to exon structure
ATRX NM_000489.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PVS1 very strong Pathogenic
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: variant classified canonical_splice, canonical_splice_consensus=true, variant_bucket='canonical_splice', apply_generic_pvs1_framework=true, suggested_default_strength='PVS1'pvs1_gene_context: germline LoF mechanism supported for ATRX (ATR-X syndrome), pvs1_gene_gate='eligible'VariantValidator normalization (prefetch.json): c.4699+2T>C maps to intron 16 ('16i') of the 36-exon NM_000489.5 transcript; RefSeq Select transcript (refseq_select=true)
pvs1_generic_framework ↗spliceai ↗gnomad_v2 ↗
✓
PM2 supporting Pathogenic
Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF 0, below the 0.1% PM2 threshold).
gnomAD v2.1 (GRCh37 X-76891404-A-G): variant absent (AF effectively 0, <0.1% threshold)gnomAD v4.1 (GRCh38 chrX-77635913-A-G): variant absent (AF effectively 0, <0.1% threshold)gnomAD-Canada v1.0: AC=0, AN=0, AF=0.0
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied
Pathogenic
PS2 Not assessed: no de novo occurrence is documented; no parental testing or parentage confirmation is available, and the variant is absent from ClinVar.
PS3 Not assessed: no functional assay evidence (RNA or protein studies) exists for this variant.
PS4 Not assessed: no case-control, cohort, or proband reports of this variant exist in ClinVar or the literature.
PM6 Not assessed: no de novo observation of this variant is documented in any individual or source.
PP1 Not assessed: no pedigree or family genotyping data exist, so segregation with disease in affected relatives cannot be evaluated.
PP3 Not met: SpliceAI predicts near-certain splice disruption (max delta 0.99), but this same prediction already underlies PVS1 and is not double-counted.
PP4 Not assessed: no proband phenotype or family-history information is available, so phenotype specificity cannot be evaluated.
PP5 Not met: no ClinVar record exists for this variant, so no expert-panel pathogenic classification is available.
Benign
BA1 Not met: allele frequency is 0 across gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >1% threshold.
BS1 Not met: allele frequency is 0 across gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >0.3% threshold.
BS2 Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with no hemizygous males or homozygous females observed.
BS3 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.
BS4 Not assessed: no family genotyping or non-segregation data exist, so absence of segregation cannot be established.
BP2 Not assessed: no phase data exist to establish cis or trans arrangement, and the X-linked inheritance makes the trans prong inapplicable.
BP4 Not met: all computational lines predict an impact (SpliceAI max delta 0.99), and no benign-direction prediction exists.
BP5 Not assessed: no proband molecular data exist, so an alternative genetic cause of disease cannot be evaluated.
BP6 Not met: no ClinVar record exists for this variant, so no expert-panel benign classification is available.
N/A · 9 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.83.
SpliceAI ↗
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
COSMIC ↗
Sources & reference links
7Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC