19-1206998-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★★).

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
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
STK11NM_000455.5 linkuse as main transcriptc.85A>T p.Ile29Phe missense_variant 1/10 ENST00000326873.12 NP_000446.1 Q15831-1A0A0S2Z4D1
STK11NM_001407255.1 linkuse as main transcriptc.85A>T p.Ile29Phe missense_variant 1/9 NP_001394184.1
STK11NR_176325.1 linkuse as main transcriptn.1221A>T non_coding_transcript_exon_variant 1/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkuse as main transcriptc.85A>T p.Ile29Phe missense_variant 1/101 NM_000455.5 ENSP00000324856.6 Q15831-1
STK11ENST00000652231.1 linkuse as main transcriptc.85A>T p.Ile29Phe missense_variant 1/9 ENSP00000498804.1 Q15831-2
STK11ENST00000585748.3 linkuse as main transcriptc.-82-11419A>T intron_variant 3 ENSP00000477641.2 A0A087WT72
STK11ENST00000593219.5 linkuse as main transcriptn.85A>T non_coding_transcript_exon_variant 1/43 ENSP00000466610.1 K7EMR0

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
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
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
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Peutz-Jeghers syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 31, 2017This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 221001). 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. 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"). This variant is not present in population databases (ExAC no frequency). 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 12, 2023The 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;.
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
Varity_R
0.47
gMVP
0.83

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs864622719; hg19: chr19-1206997; API