NM_000455.5:c.397G>A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BS1_SupportingBS2
The NM_000455.5(STK11):c.397G>A(p.Val133Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,594,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000455.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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STK11 | NM_000455.5 | c.397G>A | p.Val133Met | missense_variant | Exon 3 of 10 | ENST00000326873.12 | NP_000446.1 | |
STK11 | NM_001407255.1 | c.397G>A | p.Val133Met | missense_variant | Exon 3 of 9 | NP_001394184.1 | ||
STK11 | NR_176325.1 | n.1664G>A | non_coding_transcript_exon_variant | Exon 4 of 11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.397G>A | p.Val133Met | missense_variant | Exon 3 of 10 | 1 | NM_000455.5 | ENSP00000324856.6 | ||
STK11 | ENST00000652231.1 | c.397G>A | p.Val133Met | missense_variant | Exon 3 of 9 | ENSP00000498804.1 | ||||
STK11 | ENST00000585748.3 | c.25G>A | p.Val9Met | missense_variant | Exon 5 of 12 | 3 | ENSP00000477641.2 | |||
STK11 | ENST00000593219.5 | n.*222G>A | non_coding_transcript_exon_variant | Exon 4 of 4 | 3 | ENSP00000466610.1 | ||||
STK11 | ENST00000593219.5 | n.*222G>A | 3_prime_UTR_variant | Exon 4 of 4 | 3 | ENSP00000466610.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.00000971 AC: 14AN: 1442340Hom.: 0 Cov.: 36 AF XY: 0.00000838 AC XY: 6AN XY: 715584
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152284Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74458
ClinVar
Submissions by phenotype
Peutz-Jeghers syndrome Uncertain:5
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This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 133 of the STK11 protein (p.Val133Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 182906). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
This missense variant replaces valine with methionine at codon 133 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
This missense variant replaces valine with methionine at codon 133 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Uncertain:2
This variant is denoted STK11 c.397G>A at the cDNA level, p.Val133Met (V133M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Val133Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. STK11 Val133Met occurs at a position that is highly conserved through vertebrates and is located in the protein kinase domain (UniProt) and in the site of catalysis (Hearle 2006). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether STK11 Val133Met is pathogenic or benign. We consider it to be a variant of uncertain significance. -
BS1 -
not specified Uncertain:1
Variant summary: The c.397G>A (p.Val133Met) in STK11 gene is a missense variant involves a non-conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant is located within ATP binding site on conserved domain STKc_LKB1, however no functional studies confirming an effect of this change on the protein function were published at the time of evaluation. The variant is present in the control population dataset of ExAC and gnomAD (9.459e-05; 4/ 42290 and 0.000023; 5/215188 chrs tested, respectively with a note, that this is low quality site). The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.00001, suggesting that the variant may represent a benign polymorphism. The variant has not, to our knowledge, been reported in affected individuals via published reports but is cited as VUS by reputable databases/clinical laboratories. Due to the low quality of coverage in the general population datasents and a possibility of the variant call being deriven from a pseudogene, the variant was classified as VUS-Possibly Normal, until new information becomes available. -
STK11-related disorder Uncertain:1
The STK11 c.397G>A variant is predicted to result in the amino acid substitution p.Val133Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.015% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hepatoblastoma Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at