About KEAP1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KEAP1 c.44G>A, p.(Arg15Gln)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at very low frequency in population databases, with an overall allele frequency of 0.0155% (40/258,328 alleles) in gnomAD v2.1 and 0.0196% (310/1,579,320 alleles) in gnomAD v4.1, below the 0.1% threshold. No homozygotes are observed. The highest subpopulation frequency is in the African/African American population at 0.112% (v2.1) and 0.101% (v4.1).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.053 (well below 0.5), BayesDel score is -0.511 (below 0), and SpliceAI predicts no splicing alteration (max delta = 0.0). All in silico tools agree on a benign prediction.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
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
310 / 1,579,320 alleles
gnomAD v4.1: 310 / 1,579,320 alleles. Recorded AF 0.000196287. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000154842; MAF= 0.01548%, 40/258328 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00111977; MAF= 0.11198%, 27/24112 alleles, homozygotes = 0); grpmax FAF= 0.00070213.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KEAP1, a tumor suppressor and adaptor protein, is recurrently mutated in lung cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV50285368, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
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 · 21 not met · 1 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_012289.4:c.44G>A (p.Arg15Gln) is a missense variant in exon 2 of KEAP1, a gene in which germline variants cause autosomal dominant familial multinodular goiter.
This variant is present at very low frequency in population databases (gnomAD v2.1: 0.0155%, 40/258,328 alleles; gnomAD v4.1: 0.0196%, 310/1,579,320 alleles) with no homozygotes observed. The overall frequency is below 0.1%, meeting PM2 at a supporting level. Note that the African/African American subpopulation frequency is 0.11%, borderline above the typical 0.1% threshold.
Multiple lines of computational evidence predict a benign effect: REVEL score 0.053, BayesDel score -0.511, and SpliceAI max delta 0.0, meeting BP4 at a supporting level.
This variant has been reported once in COSMIC (COSV50285368) in a somatic cancer context and is classified as Uncertain significance in ClinVar by a single clinical laboratory (Ambry Genetics). OncoKB reports unknown oncogenic effect with no variant-specific functional evidence.
No functional studies, segregation data, de novo reports, or case-control data are available for this variant. The variant does not lie in a mutational hotspot.
The overall evidence profile includes one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), consistent with a variant of uncertain significance. Additional evidence such as functional studies, segregation analysis, case-control data, or de novo observations would be needed to refine the classification.
No criteria match.
Met · 2
PM2 SupportingThis variant is present at very low frequency in population databases, with an overall allele frequency of 0.0155% (40/258,328 alleles) in gnomAD v2.1 and 0.0196% (310/1,579,320 alleles) in gnomAD v4.1, below the 0.1% threshold. No homozygotes are observed. The highest subpopulation frequency is in the African/African American population at 0.112% (v2.1) and 0.101% (v4.1). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF = 0.0155% (40/258
- 328)
- 0 homozygotes
- grpmax FAF = 0.070%
- gnomAD v4.1: AF = 0.0196% (310/1
- 579
- 320)
- grpmax FAF = 0.082%
- Overall frequency below PM2 threshold of 0.1%
Still missing
- African/African American subpopulation frequency (0.11%) is borderline above 0.1%
- PM2 applicability may be reconsidered if ancestry matches.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.053 (well below 0.5), BayesDel score is -0.511 (below 0), and SpliceAI predicts no splicing alteration (max delta = 0.0). All in silico tools agree on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.053 (benign)
- BayesDel (no AF): -0.510705 (benign)
- SpliceAI: max delta = 0.0 (no predicted splice impact)
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No alternative nucleotide change at position c.44 resulting in the same p.Arg15Gln amino acid substitution has been established as pathogenic. No ClinVar or literature evidence supports PS1. Details ▾Hide ▴
Evidence considered
- ClinVar contains no pathogenic variant at this residue with the same amino acid change arising from a different nucleotide change.
Sources
clinvar ↗pm5_candidates
PS2 No de novo occurrence with confirmed paternity and maternity has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available in ClinVar
- literature
- or internal sources.
Still missing
- De novo testing data unavailable.
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect have been identified for NM_012289.4:c.44G>A (p.Arg15Gln). OncoKB classifies this variant as having unknown oncogenic effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies identified.
Still missing
- No functional data available for this specific variant.
Sources
PS4 No case-control studies demonstrating statistically significant enrichment of this variant in affected individuals compared to controls are available. Details ▾Hide ▴
Evidence considered
- No case-control data identified.
Still missing
- Case-control data unavailable.
PM1 This variant does not lie within a statistically significant mutational hotspot in KEAP1. Residue Arg15 is not identified as a significantly mutated residue. Details ▾Hide ▴
Evidence considered
- Hotspots analysis: exact_variant_listed = no
- residue_significant = false.
PM5 No pathogenic missense variant at the same amino acid residue (Arg15) has been identified. Automated PM5 candidate search returned no same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates
- 0 expert-panel P/LP comparators.
Sources
pm5_candidates
PM6 No de novo occurrence (without confirmed paternity and maternity) has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- De novo data unavailable.
PP1 No cosegregation data in affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data identified.
Still missing
- Segregation analysis not available.
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.053 (well below the typical damaging threshold of 0.5), BayesDel score is -0.511 (below the damaging threshold of 0), and SpliceAI predicts no splicing impact (max delta = 0.0). All in silico predictors agree on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.053 (benign-leaning)
- BayesDel: -0.510705 (benign-leaning)
- SpliceAI: max delta = 0.0 (no predicted splice impact)
Sources
PP4 No patient phenotype or family history data were provided to assess whether the clinical presentation is highly specific for KEAP1-related disease. Details ▾Hide ▴
Evidence considered
- No phenotype data available.
Still missing
- Patient phenotype information not provided.
PP5 No evidence that this variant was found in a patient with an established alternate genetic cause for disease. Details ▾Hide ▴
Evidence considered
- No data on alternative molecular diagnoses.
BA1 The overall allele frequency in gnomAD v2.1 is 0.0155%, far below the BA1 threshold of 1% (and well below 5% even in any subpopulation). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF: 0.0155%
- gnomAD v4.1 overall AF: 0.0196%
- Maximum subpopulation AF (African/African American v2.1): 0.112%
Sources
BS1 The overall allele frequency in gnomAD v2.1 is 0.0155%, below the BS1 threshold of 0.3%. Even the highest subpopulation frequency (African/African American, 0.112%) does not exceed 0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF: 0.0155% (<0.3%)
- Highest subpopulation AF: 0.112% (<0.3%)
Sources
BS2 No data are available documenting observation of this variant in healthy adult individuals for a disorder with full penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
- No healthy adult observation data available.
Still missing
- No phenotype or age data for gnomAD carriers.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect have been identified for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies identified.
Still missing
- Functional data unavailable.
BS4 No segregation data are available to evaluate lack of cosegregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- Segregation analysis not available.
BP1 KEAP1 germline disease (familial multinodular goiter) is associated with both missense and truncating variants (PMID:39373520 reports p.L136P, p.R415C, p.R483H missense variants alongside p.Q86* and p.V411fs truncating variants). Missense variants are a known disease mechanism in KEAP1, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- KEAP1 germline disease involves both missense and loss-of-function variants
- missense is an established mechanism.
Sources
pvs1_gene_context
BP2 No evidence that this variant has been observed in trans with a pathogenic variant in KEAP1 or any other fully penetrant dominant gene. Details ▾Hide ▴
Evidence considered
- No trans observation data available.
BP5 No evidence that this variant was found in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No data on alternative molecular diagnoses.
BP6 No reputable source has classified this variant as benign. ClinVar reports a single submission as Uncertain significance (Ambry Genetics, criteria provided, single submitter). Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (1 submitter). No benign assertion from a reputable source.
Sources
PS5 No evidence that this variant was found in a patient with an established alternative molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No data on alternative molecular diagnoses in carriers.
Not assessed · 1 · no assessment recorded
PP2 KEAP1 missense constraint metrics (e.g., gnomAD missense Z-score, o/e ratio) are not available in the evidence packet. Although KEAP1 germline missense variants are a known mechanism for familial multinodular goiter (PMID:39373520), the rate of benign missense variation in the gene cannot be evaluated without constraint data. Details ▾Hide ▴
Evidence considered
- KEAP1 germline missense variants are reported in familial multinodular goiter
- but no gene-level missense constraint scores are available to assess whether the gene has a low rate of benign missense variation.
Still missing
- gnomAD missense constraint metrics (Z-score
- o/e ratio) needed to evaluate PP2.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_012289.4:c.44G>A is a missense variant (p.Arg15Gln) in exon 2. It is not a null variant type (nonsense, frameshift, or canonical ±1,2 splice site) and therefore does not qualify for PVS1 under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a null variant
- variant bucket: other
- apply_generic_pvs1_framework: false.
Sources
PM3 N/AKEAP1-associated disease (familial multinodular goiter) follows autosomal dominant inheritance; PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a missense substitution, not a protein length-altering change (in-frame deletion/insertion or stop-loss). Details ▾Hide ▴
No further detail was recorded.
BP3 N/AVariant is a single-nucleotide substitution, not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_012289.4:c.44G>A is a missense variant (p.Arg15Gln), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is reserved for synonymous variants.
Identifiers
- Gene
- KEAP1
- Transcript
- NM_012289.4
- Coding (HGVS c.)
- NM_012289.4:c.44G>A
- Protein (HGVS p.)
- NP_036421.2:p.(Arg15Gln)
- GRCh38
- chr19:10499990 C>T
- GRCh37
- chr19:10610666 C>T
- ClinVar
- 2345816
- COSMIC
- COSV50285368
Gene diagram
Every interpreted variant in KEAP1, mapped onto the exon structure of NM_012289.4. Select a row to find it on the plot.
KEAP1NM_012289.4
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 KEAP1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
310 / 1,579,320 alleles
AF 0.000196 · 0 homozygotes · FAF 0.000823
gnomAD v2.1
40 / 258,328 alleles
AF 0.000155 · 0 homozygotes · FAF 0.000702
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.0002 · 310 / 1,579,320 alleles · 0 hom · FAF 0.00082
| African/African American75 / 74,518 | 0.001 |
| European (non-Finnish)214 / 1,157,622 | 0.00018 |
| Admixed American10 / 57,656 | 0.00017 |
| Remaining individuals6 / 60,898 | 9.9e-05 |
| South Asian5 / 87,572 | 5.7e-05 |
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00015 · 40 / 258,328 alleles · 0 hom · FAF 0.0007
| African/African American27 / 24,112 | 0.0011 |
| Admixed American5 / 32,816 | 0.00015 |
| South Asian2 / 26,408 | 7.6e-05 |
| European (non-Finnish)5 / 116,892 | 4.3e-05 |
| European (Finnish)1 / 23,812 | 4.2e-05 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000196287; MAF= 0.01963%, 310/1579320 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00100647; MAF= 0.10065%, 75/74518 alleles, homozygotes = 0); grpmax FAF= 0.00082258.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000154842; MAF= 0.01548%, 40/258328 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00111977; MAF= 0.11198%, 27/24112 alleles, homozygotes = 0); grpmax FAF= 0.00070213.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.053
- BayesDel
- -0.511
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.053 (well below 0.5), BayesDel score is -0.511 (below 0), and SpliceAI predicts no splicing alteration (max delta = 0.0). All in silico tools agree on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.053 (benign)
- BayesDel (no AF): -0.510705 (benign)
- SpliceAI: max delta = 0.0 (no predicted splice impact)
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.053 (well below the typical damaging threshold of 0.5), BayesDel score is -0.511 (below the damaging threshold of 0), and SpliceAI predicts no splicing impact (max delta = 0.0). All in silico predictors agree on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.053 (benign-leaning)
- BayesDel: -0.510705 (benign-leaning)
- SpliceAI: max delta = 0.0 (no predicted splice impact)
Sources
BP7 N/ANM_012289.4:c.44G>A is a missense variant (p.Arg15Gln), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is reserved for synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.053. BayesDel score = -0.510705.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
310 / 1,579,320 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Uncertain significance
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/2345816/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-10610666-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-10499990-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-10499990-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_012289.4%3Ac.44G%…
- OncoKB ↗www.oncokb.org/gene/KEAP1/R15Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120366785
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000196287; MAF= 0.01963%, 310/1579320 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00100647; MAF= 0.10065%, 75/74518 alleles, homozygotes = 0); grpmax FAF= 0.00082258.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000154842; MAF= 0.01548%, 40/258328 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00111977; MAF= 0.11198%, 27/24112 alleles, homozygotes = 0); grpmax FAF= 0.00070213.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2345816)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.053. BayesDel score = -0.510705.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KEAP1, a tumor suppressor and adaptor protein, is recurrently mutated in lung cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV50285368, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.