NM_000489.5:c.7315C>A

ATRX · NP_000480.3:p.(Pro2439Thr) · NM_000489.5

GRCh37: chrX:76763993 G>T · GRCh38: chrX:77508515 G>T

Gene: ATRX Transcript: NM_000489.5

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP6 supporting benign

Variant details

Gene

ATRX

Transcript

NM_000489.5

Protein

NP_000480.3:p.(Pro2439Thr)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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).

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	N/A	NM_000489.5:c.7315C>A is a missense variant (p.Pro2439Thr) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No evidence of a different nucleotide change at the same amino acid position (Pro2439) that is known to be pathogenic. PM5 candidate search found zero same-residue comparator variants in ClinVar.
PS2	Not assessed	No de novo observation data available for this variant. No publications report de novo occurrence of NM_000489.5:c.7315C>A.
PS3	Not assessed	No well-established functional studies are available for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications with functional data for NM_000489.5:c.7315C>A were identified.	oncokb
PS4	Not assessed	No case-control data or published patient observations specific to NM_000489.5:c.7315C>A. The GeneReviews article (PMID:20301622) is a general clinical summary of ATR-X syndrome and does not provide variant-specific prevalence data.
PS5	Not assessed	PS5 is not a standard ACMG/AMP 2015 criterion. No reputable source has reported this variant as pathogenic. The closest ClinVar entry (non-exact transcript version match) reports Likely benign, not pathogenic.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Unable to confirm same-residue pathogenic comparator variants for PM5 application. PM5 candidate search identified zero same-residue (Pro2439) comparator variants in ClinVar.	pm5_candidates
PM6	Not assessed	No de novo data available for NM_000489.5:c.7315C>A. No publications report assumed de novo occurrence without parental confirmation.
PP1	Not assessed	No cosegregation data available for this variant. No family studies have been reported.
PP2	Not assessed	HCI Prior score is not available for ATRX (gene_not_supported). Cannot calculate the rate of benign missense variation or determine whether missense variants are a common disease mechanism independent of functional domain context.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. BayesDel score is -0.166588 (below the typical damaging threshold of 0), SpliceAI max delta score is 0.00 (no predicted splicing impact), and REVEL is unavailable. The aggregate in silico evidence is consistent with a benign interpretation.	bayesdel spliceai
PP4	Not assessed	No phenotypic data have been submitted for this specific case. Cannot assess whether the patient's phenotype or family history is highly specific for ATRX-related disease.
PP5	Not assessed	No reputable source has reported this variant as pathogenic. The closest ClinVar entry (variation ID 1623753, matched to NM_000489.6:c.7429C>A, a different transcript version) reports Likely benign from a single clinical testing laboratory. This does not satisfy PP5 which requires a pathogenic assertion from a reputable source.
BA1	N/A	NM_000489.5:c.7315C>A is absent from gnomAD; the allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data available regarding observation of this variant in healthy adults for a fully penetrant disorder. No population-based penetrance studies identified.
BS3	Not assessed	No well-established functional studies are available showing no damaging effect for NM_000489.5:c.7315C>A. OncoKB reports Unknown Oncogenic Effect with no functional annotation.	oncokb
BS4	Not assessed	No segregation data available for this variant. No family studies have been reported to demonstrate lack of cosegregation with disease.
BP1	Not assessed	ATRX disease mechanism includes both truncating and missense variants. The PVS1 gene context supports loss of function as a germline disease mechanism, but missense variants are also observed in ATRX-related disorders. Without a gene-specific CSPEC/VCEP framework defining variant-type disease architecture, BP1 cannot be confidently applied.
BP2	Not assessed	No data available regarding observation of NM_000489.5:c.7315C>A in trans with a known pathogenic ATRX variant. ATRX is X-linked; BP2 is generally not applicable for X-linked genes without specific framework guidance.
BP4	Met	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 spliceai
BP5	Not assessed	No data regarding an alternate molecular basis for disease in a case carrying NM_000489.5:c.7315C>A.
BP6	Met	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
BP7	N/A	NM_000489.5:c.7315C>A is a missense variant (p.Pro2439Thr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.