NM_000489.5:c.5698-1G>C

ATRX · NP_000480.3:p.? · NM_000489.5

GRCh37: chrX:76855290 C>G · GRCh38: chrX:77599821 C>G

Gene: ATRX Transcript: NM_000489.5

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

ATRX

Transcript

NM_000489.5

Protein

NP_000480.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment spliceai gnomad_v2 gnomad_v4
PS1	N/A	PS1 applies to same amino acid change as an established pathogenic missense variant. This is a canonical splice variant with no amino acid substitution predicted.
PS2	Not met	No de novo observations have been reported for NM_000489.5:c.5698-1G>C in the literature or ClinVar.
PS3	Not met	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	Not met	No case-control or cohort enrichment data are available for this variant. The variant has not been reported in affected individuals in ClinVar or the published literature.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. No applicable framework.
PM1	Not met	This variant does not localize to a recognized mutational hotspot or critical functional domain within ATRX for which pathogenic enrichment has been established. Hotspot analysis did not identify this residue or region as significantly enriched for pathogenic variation.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 applies to a novel missense change at the same amino acid residue as an established pathogenic missense variant. This is a canonical splice variant with no missense residue context. PM5 candidate collection confirmed no same-residue comparator variants are applicable.	pm5_candidates
PM6	Not met	No de novo observations (with or without confirmed paternity) have been reported for NM_000489.5:c.5698-1G>C.
PP1	Not met	No co-segregation data are available for NM_000489.5:c.5698-1G>C in affected families.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This is a canonical splice variant, not a missense change.
PP3	Not met	SpliceAI predicts a deleterious effect on splicing (max delta 0.86, acceptor loss DS_AL=0.86). However, per ClinGen SVI PVS1 recommendations (PMC6185798), PP3 should not be stacked for the same splice-effect prediction evidence already captured by PVS1 when assessing canonical splice variants. The in silico splice evidence is incorporated into the PVS1 determination.	spliceai pvs1_variant_assessment
PP4	Not met	No patient phenotype or detailed clinical data are available for independent assessment of phenotype specificity. The variant has not been reported in ClinVar with associated phenotype information.	clinvar
PP5	Not met	No reputable source (e.g., clinical diagnostic laboratory) has reported NM_000489.5:c.5698-1G>C as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	NM_000489.5:c.5698-1G>C is absent from gnomAD v2.1 and v4.1 population databases. The allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	NM_000489.5:c.5698-1G>C is absent from gnomAD v2.1 and v4.1 population databases. The allele frequency is 0%, well below the BS1 threshold of >0.3% under generic ACMG/AMP.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of NM_000489.5:c.5698-1G>C in healthy adults. The variant is absent from all queried population databases.
BS3	Not met	No well-established functional studies demonstrating no deleterious effect for NM_000489.5:c.5698-1G>C have been identified.
BS4	Not met	No segregation data are available to evaluate lack of segregation with disease for NM_000489.5:c.5698-1G>C.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a canonical splice variant expected to cause loss of function, not a missense change.
BP2	Not met	No data are available regarding observation of NM_000489.5:c.5698-1G>C in trans with a known pathogenic ATRX variant.
BP4	Not met	Multiple lines of computational evidence predict a deleterious effect on splicing. SpliceAI predicts acceptor loss (DS_AL=0.86, max delta 0.86) and donor loss (DS_DL=0.81). BayesDel score of 0.83 also predicts a damaging effect. These computational predictions do not support BP4 (no impact on gene product).	spliceai bayesdel
BP5	Not met	No alternative molecular basis for disease has been identified in an individual carrying NM_000489.5:c.5698-1G>C. No cases with this variant and an alternative genetic cause have been reported.
BP6	Not met	No reputable source has classified NM_000489.5:c.5698-1G>C as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a canonical splice variant with strong SpliceAI evidence of splicing disruption (max delta 0.86).	spliceai

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