NM_000489.5:c.7315C>A (p.Pro2439Thr) is a missense variant in exon 35 of the ATRX gene. This variant is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).1 Multiple lines of computational evidence suggest no deleterious effect: BayesDel score of -0.166588 is in the benign range, and SpliceAI predicts no splicing impact (max delta = 0.00) (BP4_Supporting).2 A clinical testing laboratory (Invitae/Labcorp) has classified this variant as Likely benign in ClinVar (SCV002431510, criteria provided, single submitter) (BP6_Supporting). Caution: the ClinVar record matched to a different transcript version (NM_000489.6:c.7429C>A vs NM_000489.5:c.7315C>A), though these likely represent the same genomic variant.3 Under generic ACMG/AMP 2015 classification rules (PMID:25741868), the combination of two supporting benign criteria (BP4, BP6) meets the threshold for Likely Benign, despite one supporting pathogenic criterion (PM2).4
ATRX
Final classification
Likely Benign
PM2BP4BP6
ATRX
c.7315C>A
p.Pro2439Thr
This variant
NM_000489.5:c.7315C>A (p.Pro2439Thr) is a missense variant in exon 35 of the ATRX gene. This variant is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign, BP6 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP4BP6
Likely Benign
ATRX c.7315C>A
PM2 + BP4 + BP6
→
Likely Benign
2
bayesdelspliceai ↗
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 · 3 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_000489.5:c.7315C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the <0.1% allele frequency threshold for PM2. Note: ATRX is X-linked, and gnomAD population frequency interpretation requires consideration of hemizygous male ascertainment.
Absent from gnomAD v2.1v4.1and gnomAD-Canada v1.0.
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. BayesDel score is -0.166588 (benign-range prediction below the typical damaging threshold of 0), SpliceAI max delta score is 0.00 (no predicted splicing alteration), and REVEL is unavailable. The aggregate in silico prediction is consistent with a benign interpretation.
BayesDel: -0.166588 (benign-range)SpliceAI: max delta 0.00no deleterious in silico prediction.
✓
BP6
supporting
review
Benign
A reputable clinical testing laboratory (Invitae/Labcorp) has reported this variant as Likely benign in ClinVar (SCV002431510, criteria provided, single submitter). Caution: the ClinVar match was to NM_000489.6(ATRX):c.7429C>A (p.Pro2477Thr), a different transcript version, rather than the queried NM_000489.5:c.7315C>A. The two transcript versions likely represent the same genomic variant, but exact equivalence was not confirmed by the ClinVar audit. This classification reflects a single-submitter, non-expert-panel assertion.
ClinVar: Likely benignLabcorp Genetics (Invitae)SCV002431510
Assessed · not applied
· 3 not met · 15 not assessed
Pathogenic
PS1
No evidence of a different nucleotide change at the same amino acid position (Pro2439) that is known to be pathogenic.
PS2
No de novo observation data available for this variant.
PS3
No well-established functional studies are available for this variant.
PS4
No case-control data or published patient observations specific to NM_000489.5:c.7315C>A.
PM1
This variant is not located in a statistically significant mutational hotspot as determined by Cancer Hotspots analysis, nor in a well-characterized functional domain where benign variation is absent.
PM6
No de novo data available for NM_000489.5:c.7315C>A.
PP1
No cosegregation data available for this variant.
PP2
HCI Prior score is not available for ATRX (gene_not_supported).
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No phenotypic data have been submitted for this specific case.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BS1
NM_000489.5:c.7315C>A is absent from gnomAD; the allele frequency does not exceed the 0.3% BS1 threshold for an X-linked disorder.
BS2
No data available regarding observation of this variant in healthy adults for a fully penetrant disorder.
BS3
No well-established functional studies are available showing no damaging effect for NM_000489.5:c.7315C>A.
BS4
No segregation data available for this variant.
BP1
ATRX disease mechanism includes both truncating and missense variants.
BP2
No data available regarding observation of NM_000489.5:c.7315C>A in trans with a known pathogenic ATRX variant.
BP5
No data regarding an alternate molecular basis for disease in a case carrying NM_000489.5:c.7315C>A.
N/A · 4
PVS1 · PM5 · BA1 · BP7
Research & evidence
Population frequency · supports benign
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 no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.166588.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATRX, a tumor suppressor involved in transcriptional regulation, is infrequently altered in cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR