19-1226469-A-T

Variant names:

• chr19-1226469-A-T
• NM_000455.5:c.1124A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000455.5(STK11):​c.1124A>T​(p.Glu375Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

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]

ACMG classification

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 rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.1124A>T	p.Glu375Val	missense_variant	Exon 9 of 10	ENST00000326873.12	NP_000446.1
STK11	NR_176325.1	n.2391A>T		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.1124A>T	p.Glu375Val	missense_variant	Exon 9 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000585748.3	c.752A>T	p.Glu251Val	missense_variant	Exon 11 of 12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E375V variant (also known as c.1124A>T), located in coding exon 9 of the STK11 gene, results from an A to T substitution at nucleotide position 1124. The glutamic acid at codon 375 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Benign	0.16
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.72	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	.;N
REVEL	Benign	0.13
Sift	Uncertain	0.0070	.;D
Sift4G	Benign	0.10	T;T
Polyphen		0.0020	.;B
Vest4		0.58
MutPred		0.25		Loss of glycosylation at P373 (P = 0.0453);Loss of glycosylation at P373 (P = 0.0453);
MVP		0.79
MPC		0.046
ClinPred		0.85	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1226468;