NM_000455.5:c.*9G>A

STK11 · NP_000446.1:p.? · NM_000455.5

GRCh37: chr19:1226655 G>A · GRCh38: chr19:1226656 G>A

Gene: STK11 Transcript: NM_000455.5

Final call

VUS

PM2 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.?

gnomAD AF

5.953514955229568e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000455.5:c.*9G>A is a 3' UTR variant in STK11 located 9 nucleotides downstream of the stop codon.

The variant is absent from gnomAD v2.1 (0/109,868 alleles) and present at extremely low frequency in gnomAD v4.1 (9/1,511,712 alleles; AF=0.00006%), supporting application of PM2 at supporting strength.

ClinVar lists this variant under ID 387684 with mixed classifications (Likely benign from 3 laboratories, Uncertain significance from 3 laboratories, Benign from 1 laboratory) at 1-star review status, which does not meet the 3-star threshold for PP5 or BP6.

No functional studies, segregation data, de novo observations, case-control data, or phenotype information are available for this variant. No published literature mentions NM_000455.5:c.*9G>A specifically.

SpliceAI predicts no splicing impact (max delta score = 0.00), consistent with a benign splicing effect, though insufficient alone to meet BP4.

With only one pathogenic criterion met at supporting strength (PM2) and no benign criteria met, the evidence is insufficient to classify this variant beyond Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules.

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_000455.5:c.*9G>A is a 3' UTR substitution located 9 nucleotides downstream of the stop codon. It does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The PVS1 decision tree confirms the variant does not trigger generic PVS1 assessment.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	PS1 requires a different nucleotide change at the same position with a known pathogenic classification and a more severe predicted consequence. This variant is in the 3' UTR where there is no amino acid consequence hierarchy; no known pathogenic variant exists at c.*9 of STK11.
PS2	Not met	No de novo observation has been reported for NM_000455.5:c.*9G>A in any reviewed source. De novo status cannot be assessed without confirmed parent-of-origin testing for this variant.
PS3	Not met	No functional studies have been performed on NM_000455.5:c.*9G>A. The variant is located in the 3' UTR and has not been directly tested in any experimental system, nor does it fall within a systematically characterized range in any functional study.
PS4	Not met	No case-control or prevalence data are available comparing the frequency of NM_000455.5:c.*9G>A in affected individuals versus controls. The available literature consists of clinical practice guidelines and review articles that do not report variant-specific case observations.
PS5	N/A	PS5 applies when a different pathogenic missense change has been identified at the same amino acid position. NM_000455.5:c.*9G>A is a 3' UTR variant with no amino acid change (p.(=)); the paradigm does not apply.
PM1	Not met	The variant is located in the 3' UTR (c.*9), 9 nucleotides downstream of the stop codon. No evidence establishes this specific nucleotide position as a critical functional domain, mutational hotspot, or well-characterized regulatory element in STK11. No cancerhotspots.org listing exists for this variant.
PM2	Met	NM_000455.5:c.*9G>A is absent from gnomAD v2.1 (0/109,868 alleles) and present at an extremely low frequency in gnomAD v4.1 (9/1,511,712 alleles; AF=0.00006%), well below the 0.1% threshold for PM2. The variant is also absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different pathogenic missense change at the same codon. NM_000455.5:c.*9G>A is in the 3' UTR, not within the coding sequence; no codon position exists. PM5 candidate harvesting confirmed no eligible comparators.	pm5_candidates
PM6	Not met	No de novo observation of NM_000455.5:c.*9G>A with confirmed parentage has been reported. Review of available full-text publications confirms no variant-specific de novo finding.
PP1	Not met	No cosegregation data are available for NM_000455.5:c.*9G>A. None of the reviewed publications report family studies with this variant.
PP2	N/A	PP2 applies to missense variants in genes where missense variation is a known mechanism and benign missense variation is rare. NM_000455.5:c.*9G>A is a 3' UTR variant, not a missense change.
PP3	Not met	No in silico predictors support a damaging effect. REVEL and BayesDel scores are not available for this 3' UTR variant. SpliceAI predicts no splicing impact (max delta score = 0.00). No HCI prior score exists for STK11 3' UTR positions.	spliceai
PP4	Not met	No patient phenotype or clinical data are available for individuals carrying NM_000455.5:c.*9G>A. The variant's phenotype specificity for Peutz-Jeghers syndrome or other STK11-associated conditions cannot be evaluated.
PP5	Not met	ClinVar reports NM_000455.5:c.*9G>A as Likely benign (3 labs), Uncertain significance (3 labs), and Benign (1 lab) under variation ID 387684. The review status is 'criteria provided, single submitter' (1 star), which does not meet the 3-star expert panel threshold required for PP5 application. Furthermore, the ClinVar aggregate classification is Likely benign, not pathogenic.	clinvar
BA1	Not met	The maximum allele frequency of NM_000455.5:c.*9G>A in gnomAD is 0.00006% (gnomAD v4.1, 9/1,511,712 alleles), far below the 1% threshold required for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency of NM_000455.5:c.*9G>A is 0.00006% (gnomAD v4.1), far below the 0.3% threshold required for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	NM_000455.5:c.*9G>A has not been observed in a homozygous state in gnomAD (0 homozygotes in both v2.1 and v4.1). No evidence exists that this variant has been observed in healthy adults at a frequency inconsistent with pathogenicity.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating a benign effect have been performed on NM_000455.5:c.*9G>A. The variant has not been tested in any experimental system.
BS4	Not met	No segregation data are available for NM_000455.5:c.*9G>A to evaluate lack of segregation with disease.
BP1	N/A	BP1 is specific to missense variants in genes where a truncating mechanism is established. NM_000455.5:c.*9G>A is a 3' UTR substitution and does not produce a missense change.
BP2	Not met	No data are available regarding observation of NM_000455.5:c.*9G>A in trans with a known pathogenic STK11 variant.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact. The only applicable in silico tool for this 3' UTR variant is SpliceAI, which predicts no splicing impact (max delta = 0.00). However, a single line of computational evidence is insufficient to meet the 'multiple lines' requirement. REVEL and BayesDel are not available for 3' UTR positions, and no conservation data were assessed.	spliceai
BP5	N/A	BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No such data exist, and this criterion is not applicable to the current assessment.
BP6	Not met	ClinVar reports NM_000455.5:c.*9G>A as Likely benign (3 labs), Uncertain significance (3 labs), and Benign (1 lab). However, the review status is 'criteria provided, single submitter' (1 star), which falls below the 3-star expert panel threshold required to apply BP6 at supporting benign strength.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) coding variants with no predicted splicing impact. NM_000455.5:c.*9G>A is a 3' UTR variant, not a synonymous coding variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.