ATMc.8418+5_8418+8delUncertain significance

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Variant interpretation report

ATM c.8418+5_8418+8del, p.?

NM_000051.4:c.8418+5_8418+8del NP_000042.3:p.? View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About ATM

No gene-level summary was recorded for this case.

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 ClinGen ATM VCEP v1.5.0. 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: 1 Benign evidence criteria: 0

Pathogenic criteria applied · 1

PP3Supporting

PP3 · supporting

SpliceAI predicts splice impact for this intronic donor-region deletion with a maximum delta score of 0.89, which is above the ATM PP3 threshold of 0.2 for intronic variants outside the donor ±1,2 positions. This computational evidence supports an adverse splicing effect.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PP3 supporting; no rule matched the adjudicated criteria.

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

75 / 1,613,598 alleles

gnomAD v4.1: 75 / 1,613,598 alleles. Recorded AF 4.648e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.0823e-06; MAF= 0.00071%, 2/282394 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.55222e-05; MAF= 0.00155%, 2/128848 alleles, homozygotes = 0).

No listed criterion applied

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · PP3 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Context only COSMIC ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen ATM VCEP v1.5.0, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 5 not met · 8 not assessed · 14 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

Benign

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

Met Not met Not assessed Not applicable

The ATM c.8418+5_8418+8del (NP_000042.3:p.?) variant has not been reported in ClinVar.

This variant is present in gnomAD v4.1 at AF 0.00465% (75/1,613,598 alleles; grpmax FAF 0.005111%) and in gnomAD v2.1 at AF 0.00071% (2/282,394 alleles), which is above the ATM PM2_Supporting threshold of 0.001% and below the BS1 threshold of 0.05%.

SpliceAI predicts an adverse splicing effect with a maximum delta score of 0.89, which exceeds the ATM PP3 threshold of 0.2 for intronic variants outside the donor ±1,2 positions and supports PP3.

Met · 1

PP3 SupportingSpliceAI predicts splice impact for this intronic donor-region deletion with a maximum delta score of 0.89, which is above the ATM PP3 threshold of 0.2 for intronic variants outside the donor ±1,2 positions. This computational evidence supports an adverse splicing effect. Details ▾Hide ▴

Rule

ATM PP3_Supporting for splicing applies to intronic variants outside donor/acceptor ±1,2 when SpliceAI ≥0.2.

Evidence considered

Variant is outside the donor ±1
2 positions.
SpliceAI max delta score is 0.89.
ATM PP3 threshold for relevant splice prediction is SpliceAI ≥0.2.

Still missing

No direct RNA study is available to confirm the predicted splice defect.

Sources

spliceai ↗cspec ↗

Not met · 5 · evaluated, threshold not reached

PM2 This variant is present in gnomAD v4.1 at AF 0.00465% (75/1,613,598 alleles) with grpmax FAF 0.005111%, which is above the ATM PM2_Supporting threshold of 0.001%. Because the observed population frequency exceeds the VCEP rarity cutoff, PM2 is not met. Details ▾Hide ▴

Rule

PM2_Supporting requires frequency ≤0.001% in gnomAD v4.

Evidence considered

gnomAD v4.1 total AF 4.647997828455415e-05 (0.00465%)
75/1613598 alleles.
gnomAD v4.1 grpmax FAF 5.111e-05 (0.005111%).
ATM PM2 threshold is ≤0.001% in gnomAD v4.

Sources

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

PM5 For ATM, PM5_Supporting may be used for splice variants only when high-quality observed RNA evidence supports an NMD-prone splice defect meeting the truncation-cutoff framework. That level of RNA evidence is not available for this variant, so PM5 is not met. Details ▾Hide ▴

Rule

ATM PM5_Supporting for splice variants requires observed RNA evidence supporting an NMD-prone truncating outcome upstream of p.Arg3047.

Evidence considered

ATM PM5 for non-missense variants follows a truncation-cutoff rule rather than classic same-residue PM5.
PM5 candidate review marked classic same-residue PM5 as not applicable for this variant.

Still missing

No high-quality observed RNA result was identified for this variant.
NMD-prone transcript consequence has not been confirmed.

Sources

cspec ↗pm5_candidates

BA1 This variant does not meet the ATM BA1 population threshold. The gnomAD v4.1 grpmax filtering allele frequency is 0.005111%, which is far below the BA1 threshold of greater than 0.5%. Details ▾Hide ▴

Rule

BA1 requires gnomAD v4 grpmax filtering AF >0.5%.

Evidence considered

gnomAD v4.1 grpmax FAF is 5.111e-05 (0.005111%).
ATM BA1 threshold is >0.5%.

Sources

gnomad_v4 ↗cspec ↗

BS1 This variant does not meet the ATM BS1 population threshold. The gnomAD v4.1 grpmax filtering allele frequency is 0.005111%, which is below the BS1 threshold of greater than 0.05%. Details ▾Hide ▴

Rule

BS1 requires gnomAD v4 grpmax filtering AF >0.05%.

Evidence considered

gnomAD v4.1 grpmax FAF is 5.111e-05 (0.005111%).
ATM BS1 threshold is >0.05%.

Sources

gnomad_v4 ↗cspec ↗

BP4 SpliceAI predicts splice impact with a maximum delta score of 0.89, which is well above the ATM BP4 threshold of 0.1 for no predicted splice impact. Computational evidence therefore does not support BP4. Details ▾Hide ▴

Rule

BP4 for splicing requires no predicted impact with SpliceAI ≤0.1.

Evidence considered

SpliceAI max delta score is 0.89.
ATM BP4 splice threshold is SpliceAI ≤0.1.

Sources

spliceai ↗cspec ↗

Not assessed · 8 · no assessment recorded

PVS1 This intronic donor-region deletion is outside the canonical ±1,2 splice positions, so it is not covered by the default generic null-variant scaffold. ATM loss of function is an established disease mechanism, but the available evidence does not show the exact RNA consequence for this variant or confirm whether any abnormal transcript is NMD-prone under the ATM PVS1 decision framework. Details ▾Hide ▴

Rule

ATM PVS1 decision tree; non-canonical splice variants require transcript consequence review before PVS1 assignment.

Evidence considered

ATM HBOP VCEP includes a gene-specific PVS1 framework.
The variant is c.8418+5_8418+8del
outside the canonical donor ±1
2 positions.
Generic PVS1 scaffold did not place this variant into a default null-variant bucket.

Still missing

Direct RNA or other high-quality splice outcome evidence for this exact variant is not available.
The exact transcript consequence and NMD relevance have not been confirmed for this variant.

Sources

cspec ↗vcep_atm_pvs1_1_5pvs1_gene_contextpvs1_variant_assessment

PS1 No previously established pathogenic or likely pathogenic ATM splice variant with a confirmed matching splice event was identified for this variant under the ATM PS1 splicing framework. Without a qualifying reference variant in the same splice motif and evidence that the predicted event matches, PS1 cannot be assigned. Details ▾Hide ▴

Rule

ATM PS1 splicing table requires a known pathogenic or likely pathogenic splice comparator with the same predicted or observed event.

Evidence considered

ATM PS1 splicing requires a matched predicted or observed splice event relative to a known P/LP reference variant.
No exact ClinVar record was identified for this variant.

Still missing

No qualifying pathogenic or likely pathogenic comparator with a matched splice event was identified.
No variant-specific RNA data are available to confirm that this variant produces the same splice outcome as a known comparator.

Sources

cspec ↗vcep_atm_ps1_1_5clinvar ↗

PS3 No published or curated functional study for this exact variant was identified showing failure to rescue an ATM-specific functional readout or radiosensitivity. Available ATM functional supplementary tables reviewed for this case did not provide variant-specific evidence for PS3 assignment. Details ▾Hide ▴

Rule

ATM PS3 applies only with qualifying damaging functional evidence.

Evidence considered

ATM PS3 requires damaging functional evidence under the VCEP framework.
Reviewed ATM supplementary functional tables did not identify this exact variant.

Still missing

No variant-specific RNA or functional assay result was identified.
No exact entry for this variant was found in the reviewed ATM supplementary functional tables.

Sources

cspec ↗vcep_suppl_tables1_pmid_40580951vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1

PS4 No case-control study or case series for this exact variant was identified showing statistically increased prevalence in affected individuals. The currently available evidence is insufficient to support PS4. Details ▾Hide ▴

Rule

Case-control studies with p-value ≤0.05 and effect estimate meeting the ATM VCEP threshold are required.

Evidence considered

ATM PS4 requires qualifying case-control evidence.
No exact ClinVar record was identified for this variant.

Still missing

No exact-variant case-control data were identified.
No countable set of affected carriers with appropriate ascertainment was identified.

Sources

cspec ↗clinvar ↗

PM3 No proband-level evidence was identified showing this variant in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia. Therefore, no PM3 points can be assigned from the currently available evidence. Details ▾Hide ▴

Rule

ATM PM3 is assigned from accumulated proband points under the PM3/BP2 table.

Evidence considered

ATM PM3 requires point-based proband evidence for recessive disease.

Still missing

No qualifying A-T proband data were identified.
No phase-confirmed in trans observation with a pathogenic ATM variant was identified.

Sources

cspec ↗vcep_atm_pm3_bp2_1_5

PP1 No segregation data were identified for this variant. Without informative family observations, PP1 cannot be applied. Details ▾Hide ▴

Rule

AR condition: segregation in 1, 2, or ≥3 affected relatives for supporting, moderate, or strong strength.

Evidence considered

ATM PP1 requires segregation evidence in affected relatives for the relevant recessive disease context.

Still missing

No pedigree or meiosis data were identified.
No affected relative segregation data were identified.

European (non-Finnish)74 / 1,179,808	6.3e-05
African/African American1 / 74,856	1.3e-05