Classification rationale

PP3 VUS

ATM c.8418+5_8418+8del

The ATM c.8418+5_8418+8del (NP_000042.3:p.?) variant has not been reported in ClinVar.¹ 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%.² 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 PP3.³

PP3 → VUS

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 spliceai ↗cspec ↗

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.

Gene diagram · NM_000051.4 · variants mapped to exon structure

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 13 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

PP3 supporting review Pathogenic

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.

Variant is outside the donor ±12 positions.SpliceAI max delta score is 0.89.

spliceai ↗cspec ↗

Assessed · not applied · 5 not met · 8 not assessed

Pathogenic

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.

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.

PS3 No published or curated functional study for this exact variant was identified showing failure to rescue an ATM-specific functional readout or radiosensitivity.

PS4 No case-control study or case series for this exact variant was identified showing statistically increased prevalence in affected individuals.

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%.

PM3 No proband-level evidence was identified showing this variant in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia.

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.

PP1 No segregation data were identified for this variant.

Benign

BA1 This variant does not meet the ATM BA1 population threshold.

BS1 This variant does not meet the ATM BS1 population threshold.

BS3 No published or curated evidence was identified showing preserved splicing or preserved ATM function for this exact variant.

BP2 No evidence was identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an unaffected adult without ataxia-telangiectasia, and no qualifying co-occurrence evidence in cis was identified.

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.

N/A · 14 PS2 · PM1 · PM4 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 4.648e-05; MAF= 0.00465%, 75/1613598 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.27221e-05; MAF= 0.00627%, 74/1179808 alleles, homozygotes = 0); grpmax FAF= 5.111e-05.

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).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0046% · 75 / 1,613,598
0 hom · FAF 0.0051%

European (non-Finnish) 74 / 1,179,808	0.0063%
African/African American 1 / 74,856	0.0013%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.00071% · 2 / 282,394
0 hom

European (non-Finnish)

2 / 128,848

0.0016%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.89).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

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

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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