ATRXc.4434_4435delNot classified

Print report

Variant interpretation report

ATRX c.4434_4435del, p.(Lys1479AsnfsTer6)

NM_000489.5:c.4434_4435del NP_000480.3:p.(Lys1479AsnfsTer6) View identifiers

Classification

Not classified

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. Select a step to read what it means.

Not classified yet.Select a step to read what it means.

In plain language

Gene-level background from the recorded interpretation.

About ATRX

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 2 moderate (pathogenic)
Expert rules: Not recorded
Pipeline record: 30 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (strong): 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.
PM1 (moderate): 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.
PM2 (moderate): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PVS1Strong

PVS1 · strong

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.

PM1Moderate

PM1 · moderate

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.

PM2Moderate

PM2 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Not classified

No source classification-combination explanation was recorded.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

In progress — evidence not uploaded yet.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 16 not met · 1 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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.

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.

The variant is absent from all gnomAD populations (v2.1, v4.1, Canada), consistent with rarity in the general population.

No functional studies, clinical observations, segregation data, or variant-specific publications were identified for this specific variant.

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.

Met · 3

PVS1 StrongThis 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. Details ▾Hide ▴

Evidence considered

Frameshift deletion in exon 15 of 35 exons
predicted NMD target
ATRX loss-of-function mechanism established for germline disease (ATR-X syndrome)
Known rescue mechanisms for ATRX N-terminal truncations (R37X
exon 10 cluster) do not apply at this downstream position

Sources

pvs1_generic_frameworkpvs1_gene_contextpvs1_variant_assessmentPMID:15591283 ↗PMID:18409179 ↗

PM1 ModerateThis 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. Details ▾Hide ▴

Evidence considered

The helicase/ATPase domain is a critical functional domain in ATRX
harboring ~30% of disease-associated missense mutations (PMID:18409179)
Frameshift truncation at p.1479 removes the entire helicase domain and C-terminal region

Sources

PMID:18409179 ↗PMID:17609377 ↗

PM2 ModerateThis 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. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (all populations)
Absent from gnomAD v4.1 (all populations)
Absent from gnomAD-Canada v1.0

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 16 · evaluated, threshold not reached

PS2 No de novo observation reported for this variant in any reviewed source. The variant has not been described in any clinical or research publication. Details ▾Hide ▴

Still missing

No clinical reports of this variant exist to assess de novo status

PS3 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. Details ▾Hide ▴

Evidence considered

OncoKB 'Likely Loss-of-function' annotation is derived from variant consequence prediction
not experimental functional data

Still missing

No experimental functional data exists for this specific variant
No saturation mutagenesis or systematic truncation series covering position 1479

Sources

oncokb ↗

PS4 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. Details ▾Hide ▴

Evidence considered

Variant is absent from ClinVar
no clinical submissions or case reports exist

Still missing

No clinical or population case data for this variant

Sources

clinvar ↗

PM6 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. Details ▾Hide ▴

Still missing

No de novo reports exist for this variant

PP1 No segregation data are available. This variant has not been identified in any family study. Details ▾Hide ▴

Still missing

No familial segregation data

PP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.04 (no predicted splicing impact)
REVEL and BayesDel not available (non-SNV variant)

Sources

spliceai ↗

PP5 This variant is absent from ClinVar. No reputable source (ClinVar 3-star expert panel or greater) has classified it as pathogenic. Details ▾Hide ▴

Evidence considered

Variant is absent from ClinVar
no pathogenic classification exists from any source

Sources

clinvar ↗

BA1 This variant is absent from all gnomAD populations (allele frequency = 0.0%). BA1 requires an allele frequency >1%, which is not met. Details ▾Hide ▴

Evidence considered

Variant is absent from gnomAD v2.1 and v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 This variant is absent from all gnomAD populations (allele frequency = 0.0%). BS1 requires an allele frequency >0.3%, which is not met. Details ▾Hide ▴

Evidence considered

Variant is absent from gnomAD v2.1 and v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 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. Details ▾Hide ▴

Still missing

No population data in healthy male controls for this variant

BS3 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. Details ▾Hide ▴

Still missing

No functional studies demonstrating neutral effect

BS4 No segregation data are available to evaluate lack of cosegregation with disease. Details ▾Hide ▴

Still missing

No familial segregation data

BP2 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. Details ▾Hide ▴

Still missing

No observation in trans with a pathogenic variant

BP4 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.04 (no significant splicing impact)
Only one line of computational evidence available
multiple lines required for BP4

Sources

spliceai ↗

BP5 This variant has not been observed in any individual with an alternative molecular basis for disease. No clinical cases reported. Details ▾Hide ▴

Still missing

No clinical observations for this variant

BP6 This variant is absent from ClinVar. No reputable source has classified it as benign. Details ▾Hide ▴

Evidence considered

Variant is absent from ClinVar
no benign classification from any source

Sources

clinvar ↗

Not assessed · 1 · no assessment recorded

PP4 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. Details ▾Hide ▴

Still missing

Patient phenotype and clinical context are not available for this assessment

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped per instructions. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 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. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. This variant is itself a truncating (frameshift) variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without a known function. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous or intronic variants predicted to have no splice impact. This is a frameshift deletion, not a synonymous or intronic variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: ATRX
Transcript: NM_000489.5
Coding (HGVS c.): NM_000489.5:c.4434_4435del
Protein (HGVS p.): NP_000480.3:p.(Lys1479AsnfsTer6)
GRCh38: chrX:77652235 TTC>T
GRCh37: chrX:76907725 TTC>T

Gene diagram

Every interpreted variant in ATRX, mapped onto the exon structure of NM_000489.5. Select a row to find it on the plot.

ATRXNM_000489.5

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in ATRX — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +118 bp

0.010

SpliceAI acceptor gainat -158 bp

0.040

SpliceAI donor lossat +230 bp

0.000

SpliceAI donor gainat -252 bp

0.020

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.020

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta score = 0.04 (no predicted splicing impact)
REVEL and BayesDel not available (non-SNV variant)

Sources

spliceai ↗

Evidence considered

SpliceAI max delta score = 0.04 (no significant splicing impact)
Only one line of computational evidence available
multiple lines required for BP4

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous or intronic variants predicted to have no splice impact. This is a frameshift deletion, not a synonymous or intronic variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

In progress — evidence not uploaded yet.

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Acquired somatic ATRX mutations in myelodysplastic syndrome associated with alpha thalassemia (ATMDS) convey a more severe hematologic phenotype than germline ATRX mutations.

No paper-specific finding is recorded.

PMID 14592816 ↗
Attenuation of an amino-terminal premature stop codon mutation in the ATRX gene by an alternative mode of translational initiation.

No paper-specific finding is recorded.

PMID 15591283 ↗
Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX.

No paper-specific finding is recorded.

PMID 17609377 ↗
Mutations in the chromatin-associated protein ATRX.

No paper-specific finding is recorded.

PMID 18409179 ↗
Altered telomeres in tumors with ATRX and DAXX mutations.

No paper-specific finding is recorded.

PMID 21719641 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.040 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

In progress — evidence not uploaded yet.

In silico

In progress — evidence not uploaded yet.

Functional

In progress — evidence not uploaded yet.

Somatic

In progress — evidence not uploaded yet.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Literature

In progress — evidence not uploaded yet.