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ATRc.5459_5460insCLikely pathogenic
Print report
Variant interpretation report

ATR c.5459_5460insC, p.(Asp1821Ter)

NM_001184.3:c.5459_5460insC NP_001175.2:p.(Asp1821Ter) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About ATR

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 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

Nonsense variant (p.Asp1821Ter) in ATR, where loss-of-function is an established disease mechanism for Seckel syndrome. The premature termination codon at position 1821 of 2645 resides well upstream of the last exon; nonsense-mediated decay is expected. Under ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at very strong evidence level.

PM2Moderate
PM2 · moderate

NM_001184.3:c.5459_5460insC is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare pathogenic variant. Under generic ACMG/AMP 2015, absence from population databases supports PM2 at moderate strength.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

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

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. 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

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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: 2 met · 10 not met · 8 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001184.3:c.5459_5460insC (p.Asp1821Ter) is a nonsense variant in ATR, where loss-of-function is an established mechanism for Seckel syndrome type 1. The premature termination codon at position 1821 of 2645 is expected to trigger nonsense-mediated decay, satisfying PVS1 at very strong evidence level under ClinGen SVI PVS1 recommendations (PMC6185798).

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting PM2 at moderate evidence level.

No benign criteria are met. BA1 and BS1 are not satisfied (allele frequency 0%). BS2, BS3, BS4, BP2, BP4, BP5, and BP6 are not met or not assessed due to insufficient data.

Under generic ACMG/AMP 2015 combination rules (PMID:25741868), one very strong criterion (PVS1) plus one moderate criterion (PM2) supports a Likely Pathogenic classification.

Met · 2

PVS1 Very strongNonsense variant (p.Asp1821Ter) in ATR, where loss-of-function is an established disease mechanism for Seckel syndrome. The premature termination codon at position 1821 of 2645 resides well upstream of the last exon; nonsense-mediated decay is expected. Under ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at very strong evidence level. Details ▾Hide ▴
Evidence considered
  • Nonsense variant p.Asp1821Ter (NP_001175.2:p.(D1821*)) predicted to trigger nonsense-mediated decay
  • ATR loss-of-function is an established germline disease mechanism (Seckel syndrome type 1)
  • Variant is not in the last exon
  • multiple downstream exons present
  • supporting NMD
Still missing
  • No direct RNA or protein-level evidence confirming NMD for this specific variant
  • No CSPEC/VCEP-specific PVS1 framework for ATR
  • assessment relies on generic PMC6185798 fallback
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 ModerateNM_001184.3:c.5459_5460insC is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare pathogenic variant. Under generic ACMG/AMP 2015, absence from population databases supports PM2 at moderate strength. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent (AF=0)
  • gnomAD v4.1: absent (AF=0)
  • gnomAD-Canada v1.0: absent (AF=0.0
  • AN=0)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 10 · evaluated, threshold not reached

PM1 The variant does not lie in a statistically significant mutational hotspot or a well-characterized critical functional domain without benign variation, per cancerhotspots.org analysis. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots analysis: residue not significant
  • exact variant not listed
PP3 No in silico prediction tools (REVEL, BayesDel) provide scores for insertion variants. SpliceAI predicts no splice impact (max delta score 0.00). Multiple lines of computational evidence supporting a deleterious effect are not satisfied. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta 0.00
  • no predicted splice alteration
  • REVEL/BayesDel/HCI prior: not available for insertion variants
Sources
spliceai ↗
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Population allele frequency is 0% across all queried databases
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from population databases. Allele frequency is 0%, well below the BS1 threshold of >0.3% for a rare disease. Details ▾Hide ▴
Evidence considered
  • Population allele frequency is 0% across all queried databases
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 The variant has not been observed in healthy adult individuals to satisfy BS2 criteria. Its absence from all population databases precludes application of this criterion. Details ▾Hide ▴

No further detail was recorded.

BS4 No family studies demonstrating lack of segregation between this variant and disease have been reported. In the absence of such data, BS4 cannot be applied. Details ▾Hide ▴
Still missing
  • No segregation data available to assess BS4
BP2 No observation of this variant in trans with a pathogenic ATR variant in a healthy individual, or in cis with a pathogenic variant, has been reported. The variant's extreme rarity precludes such observations. Details ▾Hide ▴
Still missing
  • No observations in trans or cis with established pathogenic variants
BP4 Multiple lines of computational evidence suggesting no impact are not satisfied. SpliceAI predicts no splice alteration (delta 0.00), but REVEL and BayesDel are unavailable for insertion variants, leaving only one line of computational evidence instead of the multiple required for BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.00: no predicted splice impact
  • REVEL/BayesDel not available for insertions
Sources
spliceai ↗
BP5 No observation of this variant in a case where an alternative molecular basis for the disease has been identified. Details ▾Hide ▴
Still missing
  • No co-occurrence with an alternate molecular diagnosis reported
BP6 No reputable source has classified this variant as benign or likely benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification available
Sources
clinvar ↗

Not assessed · 8 · no assessment recorded

PS2 No confirmed de novo occurrence with established maternity and paternity has been reported for NM_001184.3:c.5459_5460insC. The variant is absent from ClinVar and no family studies identifying a de novo event were identified. Details ▾Hide ▴
Still missing
  • No trio or family-based sequencing studies reporting this variant as de novo
PS3 No variant-specific functional studies demonstrating a damaging effect on ATR protein function were identified. Available publications (PMID:10691732, PMID:15282542) discuss ATR loss-of-function at the gene level but do not mention NM_001184.3:c.5459_5460insC. Details ▾Hide ▴
Still missing
  • No functional assays (e.g.
  • kinase activity
  • NMD validation) performed on this specific variant
  • PMID:10691732 and PMID:15282542 provide gene-level LOF evidence but lack variant-specific data
Sources
1069173215282542
PS4 No case-control study comparing the prevalence of this variant in affected versus unaffected individuals is available. The variant is absent from gnomAD and ClinVar, precluding statistical enrichment analysis. Details ▾Hide ▴
Still missing
  • No study has compared frequency of this variant between cases and controls
  • Extreme rarity precludes statistical power for PS4
PM6 No de novo observation (assumed or confirmed) has been reported for this variant. For the autosomal recessive Seckel syndrome, a single de novo heterozygous variant would not be sufficient; PM6 is rarely applicable in this context. Details ▾Hide ▴
Still missing
  • No trio sequencing data reporting this variant as de novo
PP1 No co-segregation data are available for this variant. No family with multiple affected members carrying this variant has been reported. Details ▾Hide ▴
Still missing
  • No published pedigree demonstrating co-segregation with disease
PP4 No detailed patient phenotype information is available for individuals carrying this variant. Without specific phenotype data, the specificity of the patient's presentation cannot be evaluated. Details ▾Hide ▴
Still missing
  • No clinical phenotype data available for carriers of this variant
PP5 No reputable source (e.g., clinical diagnostic laboratory) has independently classified NM_001184.3:c.5459_5460insC. The variant is absent from ClinVar. Details ▾Hide ▴
Still missing
  • Variant is absent from ClinVar
  • no external expert classification available
BS3 No variant-specific functional studies demonstrating no damaging effect on ATR protein function are available. Gene-level functional studies (PMID:10691732, PMID:15282542) establish ATR loss-of-function as pathogenic, which supports pathogenicity rather than benignity. Details ▾Hide ▴
Still missing
  • No functional assay results for this specific variant
  • Available gene-level data support a deleterious LOF mechanism
Sources
1069173215282542
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 requires a nucleotide substitution that predicts the same amino acid change as an established pathogenic missense variant. This variant is a 1-bp insertion causing a frameshift and premature termination, not a substitution. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped by directive. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is a frameshift insertion leading to a premature termination codon, assessed under PVS1. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a different pathogenic missense change at the same codon. This variant creates a premature termination codon at Asp1821, and no qualifying same-residue comparator variants were identified in the PM5 candidate search. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. This variant is a frameshift insertion producing a nonsense change, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is itself a truncating (nonsense) variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. This variant is a frameshift insertion leading to a premature termination codon, not an in-frame indel. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift insertion causing a premature termination codon, not a synonymous change. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 applies when a variant is assumed de novo with unconfirmed parentage. No de novo observation, assumed or confirmed, has been reported for this variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
ATR
Transcript
NM_001184.3
Coding (HGVS c.)
NM_001184.3:c.5459_5460insC
Protein (HGVS p.)
NP_001175.2:p.(Asp1821Ter)
GRCh38
chr3:142498695 A>AG
GRCh37
chr3:142217537 A>AG

Gene diagram

Every interpreted variant in ATR, mapped onto the exon structure of NM_001184.3. Select a row to find it on the plot.

ATRNM_001184.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

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.

SpliceAI and Pangolin

SpliceAI acceptor lossat +79 bp
0.000
SpliceAI acceptor gainat -47 bp
0.000
SpliceAI donor lossat -93 bp
0.000
SpliceAI donor gainat -15 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 No in silico prediction tools (REVEL, BayesDel) provide scores for insertion variants. SpliceAI predicts no splice impact (max delta score 0.00). Multiple lines of computational evidence supporting a deleterious effect are not satisfied. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta 0.00
  • no predicted splice alteration
  • REVEL/BayesDel/HCI prior: not available for insertion variants
Sources
spliceai ↗
BP4 Multiple lines of computational evidence suggesting no impact are not satisfied. SpliceAI predicts no splice alteration (delta 0.00), but REVEL and BayesDel are unavailable for insertion variants, leaving only one line of computational evidence instead of the multiple required for BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.00: no predicted splice impact
  • REVEL/BayesDel not available for insertions
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift insertion causing a premature termination codon, not a synonymous change. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

2 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

  • ATR disruption leads to chromosomal fragmentation and early embryonic lethality.
    Demonstrates that complete ATR loss causes chromosomal fragmentation and early embryonic lethality in mice. ATR(-/-) blastocysts accumulate caspase-independent chromosome breaks before undergoing caspase-dependent apoptosis, establishing ATR as essential for early embryonic development. NM_001184.3:c.5459_5460insC (p.Asp1821Ter) was not identified in this paper.
    Does not name this variant
    PMID 10691732 ↗
    Quoted passage
    ATR(-/-) embryos die early in development, subsequent to the blastocyst stage and prior to 7.5 days p.c.

    Abstract only; no full text available

  • ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background.
    Shows that monoallelic ATR inactivation on an MMR-deficient background causes hypersensitivity to genotoxic stress, fragile site instability, and chromosomal rearrangements in HCT 116 cells. Atr(+/-)/Mlh1(-/-) mice exhibit embryonic lethality and early tumor development, demonstrating ATR functions as a gene dosage-dependent tumor suppressor. NM_001184.3:c.5459_5460insC (p.Asp1821Ter) was not identified in this paper.
    Does not name this variant
    PMID 15282542 ↗
    Quoted passage
    mice bearing the same Atr(+/-)/Mlh1(-/-) genotype were highly prone to both embryonic lethality and early tumor development

    Abstract only; no full text available

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 0.000 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

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.