LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-30
Case ID: NM_000489.5_c.4434_4435del_20260730_032545
Framework: ACMG/AMP 2015
Variant classification summary

ATRX  · NP_000480.3:p.(Lys1479AsnfsTer6)  · NM_000489.5
GRCh37: chrX:76907725 TTC>T  ·  GRCh38: chrX:77652235 TTC>T
Gene: ATRX Transcript: NM_000489.5
Final call
All criteria require review: For research and educational purposes only.
Variant details
Gene
ATRX
Transcript
NM_000489.5
Protein
NP_000480.3:p.(Lys1479AsnfsTer6)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_000489.5:c.4434_4435del (p.Lys1479AsnfsTer6) is a frameshift deletion in exon 15 of the ATRX gene, predicted to trigger nonsense-mediated decay and result in complete loss of the C-terminal helicase domain and approximately 1,000 C-terminal amino acids.
2
ATRX loss of function is an established disease mechanism for ATR-X syndrome, an X-linked disorder characterized by developmental delay, facial dysmorphism, genital abnormalities, and alpha thalassemia.
3
The helicase/ATPase domain (aa ~1205-1863) is a critical functional domain in ATRX, harboring approximately 30% of all disease-associated missense mutations. This frameshift removes the entire helicase domain.
4
The variant is absent from all gnomAD populations (v2.1, v4.1, Canada), consistent with rarity in the general population.
5
No functional studies, clinical observations, segregation data, or variant-specific publications were identified for this specific variant.
6
Five publications retrieved via OncoKB were reviewed in full text; none mention NM_000489.5:c.4434_4435del. These papers address general ATRX biology including the ADD domain structure, R37X translational rescue, mutation spectrum, and ALT phenotype in PanNETs.
Final determination:
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 This frameshift deletion (NM_000489.5:c.4434_4435del, p.Lys1479AsnfsTer6) in exon 15 of 35 is predicted to undergo nonsense-mediated decay. ATRX loss of function is an established germline disease mechanism, supported by ATR-X syndrome and the gene-level PVS1 gate confirming eligibility under PMC6185798. No evidence of translational rescue was found for this specific variant location; known rescue mechanisms (e.g., R37X via downstream initiation) are limited to N-terminal mutations and do not extend to exon 15.
pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:15591283 PMID:18409179
PS1 N/A PS1 requires a different nucleotide substitution at the same position producing the same amino acid change. This variant is a frameshift deletion, not a missense substitution.
PS2 Not met No de novo observation reported for this variant in any reviewed source. The variant has not been described in any clinical or research publication.
PS3 Not met No functional studies directly testing NM_000489.5:c.4434_4435del or a systematically characterized range covering position 1479 were identified. OncoKB annotation of 'Likely Loss-of-function' is based on variant type (frameshift) rather than experimental functional data. The five reviewed papers address ATRX biology (ADD domain structure, R37X rescue, ALT phenotype) but none provide variant-specific functional evidence for c.4434_4435del.
oncokb
PS4 Not met This variant is absent from ClinVar and has not been reported in any case-control study or clinical cohort. No published case observations were identified.
clinvar
PS5 N/A PS5 applies to novel missense variants at the same amino acid position as a known pathogenic missense change. This is a frameshift deletion, not a missense variant.
PM1 Met This frameshift deletion at p.Lys1479 results in premature termination (p.Lys1479AsnfsTer6) that removes the C-terminal helicase/ATPase domain (aa ~1205-1863), a well-characterized critical functional domain in ATRX. The helicase domain harbors approximately 30% of all disease-associated ATRX missense mutations and is essential for chromatin remodeling activity. The truncation eliminates all helicase motifs along with approximately 1,000 C-terminal residues.
PMID:18409179 PMID:17609377
PM2 Met This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). The allele frequency of 0.0% is well below the PM2 threshold of <0.1% for a gene without a VCEP-specific frequency cutoff.
gnomad_v2 gnomad_v4 gnomad_canada
PM3 N/A Skipped per instructions.
PM4 N/A PM4 applies to in-frame deletions/insertions in nonrepeat regions or stop-loss variants. This is a frameshift deletion that introduces a premature termination codon; the null effect is already captured by PVS1.
PM5 N/A PM5 requires a novel missense change at the same amino acid residue as a known pathogenic missense variant. This is a frameshift deletion; same-residue comparator semantics cannot be established for a frameshift.
PM6 Not met No de novo observation (with confirmed maternity and paternity) has been reported for this variant. The variant does not appear in any clinical publication or database.
PP1 Not met No segregation data are available. This variant has not been identified in any family study.
PP2 N/A PP2 applies to missense variants in genes with a low rate of benign missense variation where missense mutations are a common disease mechanism. This variant is a frameshift deletion.
PP3 Not met SpliceAI predicts no significant splice impact (max delta score = 0.04, well below the 0.2 threshold). REVEL and BayesDel scores are not applicable for this non-SNV variant. No in silico evidence supports a deleterious effect at the level required for PP3.
spliceai
PP4 Not assessed PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No clinical phenotype or patient context was provided for this variant assessment.
PP5 Not met This variant is absent from ClinVar. No reputable source (ClinVar 3-star expert panel or greater) has classified it as pathogenic.
clinvar
BA1 Not met This variant is absent from all gnomAD populations (allele frequency = 0.0%). BA1 requires an allele frequency >1%, which is not met.
gnomad_v2 gnomad_v4
BS1 Not met This variant is absent from all gnomAD populations (allele frequency = 0.0%). BS1 requires an allele frequency >0.3%, which is not met.
gnomad_v2 gnomad_v4
BS2 Not met No hemizygous observation of this variant has been reported in unaffected male controls. ATRX is X-linked; hemizygous presence in healthy males would provide evidence for a benign role, but no such data exist.
BS3 Not met No functional studies demonstrating a neutral or benign effect of this variant exist. OncoKB annotates this variant as 'Likely Loss-of-function', consistent with a damaging rather than benign effect.
BS4 Not met No segregation data are available to evaluate lack of cosegregation with disease.
BP1 N/A BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. This variant is itself a truncating (frameshift) variant.
BP2 Not met This variant has not been observed in trans with a known pathogenic ATRX variant. Given that ATRX is X-linked and primarily affects hemizygous males, BP2 is less applicable but no supporting data exist.
BP3 N/A BP3 applies to in-frame deletions or insertions in repetitive regions without a known function. This is a frameshift deletion.
BP4 Not met BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. SpliceAI max delta = 0.04 (no splicing impact) is the only available computational result; REVEL and BayesDel are not applicable for this non-SNV variant. A single benign SpliceAI score does not constitute the multiple lines of evidence required for BP4.
spliceai
BP5 Not met This variant has not been observed in any individual with an alternative molecular basis for disease. No clinical cases reported.
BP6 Not met This variant is absent from ClinVar. No reputable source has classified it as benign.
clinvar
BP7 N/A BP7 applies to synonymous or intronic variants predicted to have no splice impact. This is a frameshift deletion, not a synonymous or intronic variant.
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