NM_012289.4:c.44G>A

KEAP1 · NP_036421.2:p.(Arg15Gln) · NM_012289.4

GRCh37: chr19:10610666 C>T · GRCh38: chr19:10499990 C>T

Gene: KEAP1 Transcript: NM_012289.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

KEAP1

Transcript

NM_012289.4

Protein

NP_036421.2:p.(Arg15Gln)

gnomAD AF

0.00019628700959906795 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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).	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework
PS1	Not met	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.	clinvar pm5_candidates
PS2	Not met	No de novo occurrence with confirmed paternity and maternity has been reported for this variant.
PS3	Not met	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.	oncokb
PS4	Not met	No case-control studies demonstrating statistically significant enrichment of this variant in affected individuals compared to controls are available.
PS5	Not met	No evidence that this variant was found in a patient with an established alternative molecular basis for disease.
PM1	Not met	This variant does not lie within a statistically significant mutational hotspot in KEAP1. Residue Arg15 is not identified as a significantly mutated residue.
PM2	Met	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).	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Arg15) has been identified. Automated PM5 candidate search returned no same-residue comparator variants.	pm5_candidates
PM6	Not met	No de novo occurrence (without confirmed paternity and maternity) has been reported for this variant.
PP1	Not met	No cosegregation data in affected family members is available for this variant.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data were provided to assess whether the clinical presentation is highly specific for KEAP1-related disease.
PP5	Not met	No evidence that this variant was found in a patient with an established alternate genetic cause for disease.
BA1	Not met	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).	gnomad_v2 gnomad_v4
BS1	Not met	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%.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available documenting observation of this variant in healthy adult individuals for a disorder with full penetrance expected at an early age.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect have been identified for this variant.
BS4	Not met	No segregation data are available to evaluate lack of cosegregation with disease in affected family members.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	No evidence that this variant has been observed in trans with a pathogenic variant in KEAP1 or any other fully penetrant dominant gene.
BP4	Met	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.	revel bayesdel spliceai
BP5	Not met	No evidence that this variant was found in a case with an alternative molecular basis for disease.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar reports a single submission as Uncertain significance (Ambry Genetics, criteria provided, single submitter).	clinvar
BP7	N/A	NM_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.
BP3	N/A	Variant is a single-nucleotide substitution, not an in-frame deletion or insertion in a repetitive region.
PM3	N/A	KEAP1-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.
PM4	N/A	Variant is a missense substitution, not a protein length-altering change (in-frame deletion/insertion or stop-loss).

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