NM_000455.5:c.85A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000455.5(STK11):​c.85A>T​(p.Ile29Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I29I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.82

Publications

1 publications found
Variant links:
Genes affected
STK11 (HGNC:11389): (serine/threonine kinase 11) The protein encoded by this gene is a serine/threonine kinase that regulates cell polarity and energy metabolism and functions as a tumor suppressor. Mutations in this gene have been associated with the autosomal dominant Peutz-Jeghers syndrome, as well as with skin, pancreatic, and testicular cancers. [provided by RefSeq, May 2022]
STK11 Gene-Disease associations (from GenCC):
  • familial pancreatic carcinoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • Peutz-Jeghers syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
  • familial ovarian cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STK11NM_000455.5 linkc.85A>T p.Ile29Phe missense_variant Exon 1 of 10 ENST00000326873.12 NP_000446.1 Q15831-1A0A0S2Z4D1
STK11NM_001407255.1 linkc.85A>T p.Ile29Phe missense_variant Exon 1 of 9 NP_001394184.1
STK11NR_176325.1 linkn.1221A>T non_coding_transcript_exon_variant Exon 1 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkc.85A>T p.Ile29Phe missense_variant Exon 1 of 10 1 NM_000455.5 ENSP00000324856.6 Q15831-1
STK11ENST00000652231.1 linkc.85A>T p.Ile29Phe missense_variant Exon 1 of 9 ENSP00000498804.1 Q15831-2
STK11ENST00000593219.6 linkn.85A>T non_coding_transcript_exon_variant Exon 1 of 11 3 ENSP00000466610.1 K7EMR0
STK11ENST00000585748.3 linkc.-82-11419A>T intron_variant Intron 3 of 11 3 ENSP00000477641.2 A0A087WT72

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461386
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726956
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44698
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86230
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53224
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111808
Other (OTH)
AF:
0.00
AC:
0
AN:
60354
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Peutz-Jeghers syndrome Uncertain:1
Oct 31, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces isoleucine with phenylalanine at codon 29 of the STK11 protein (p.Ile29Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 221001). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1
Jun 12, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.I29F variant (also known as c.85A>T), located in coding exon 1 of the STK11 gene, results from an A to T substitution at nucleotide position 85. The isoleucine at codon 29 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Benign
0.37
T;D;T
Eigen
Benign
0.024
Eigen_PC
Benign
0.14
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Pathogenic
0.29
D
MetaRNN
Uncertain
0.57
D;D;D
MetaSVM
Uncertain
-0.013
T
MutationAssessor
Uncertain
2.0
.;M;.
PhyloP100
8.8
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-2.8
.;D;.
REVEL
Uncertain
0.42
Sift
Benign
0.093
.;T;.
Sift4G
Benign
0.067
T;T;T
Polyphen
0.022
.;B;.
Vest4
0.68
MutPred
0.44
Loss of stability (P = 0.0807);Loss of stability (P = 0.0807);Loss of stability (P = 0.0807);
MVP
0.67
MPC
2.4
ClinPred
0.96
D
GERP RS
3.9
PromoterAI
-0.014
Neutral
Varity_R
0.47
gMVP
0.83
Mutation Taster
=63/37
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs864622719; hg19: chr19-1206997; API