NM_000455.5:c.597+1G>A

Variant names:

• chr19-1220506-G-A
• rs886039554
• NM_000455.5:c.597+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000455.5(STK11):​c.597+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.86
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1220506-G-A is Pathogenic according to our data. Variant chr19-1220506-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1750786.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.597+1G>A		splice_donor_variant, intron_variant	Intron 4 of 9	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.597+1G>A		splice_donor_variant, intron_variant	Intron 4 of 8		NP_001394184.1
STK11	NR_176325.1	n.1864+1G>A		splice_donor_variant, intron_variant	Intron 5 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.597+1G>A		splice_donor_variant, intron_variant	Intron 4 of 9	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.597+1G>A		splice_donor_variant, intron_variant	Intron 4 of 8			ENSP00000498804.1
STK11	ENST00000585748.3	c.225+1G>A		splice_donor_variant, intron_variant	Intron 6 of 11	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*422+1G>A		splice_donor_variant, intron_variant	Intron 5 of 10	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 01, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.597+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the STK11 gene. This alteration was identified in a mother and daughter with a clinical diagnosis of Peutz-Jeghers syndrome; cDNA analysis performed demonstrated this alteration causes skipping of exon 4 (Papp J et al. BMC Med. Genet. 2010 Nov;11:169). Two other alterations at this nucleotide (c.597+1G>T and c.597+1G>C) have also been described in patients with Peutz-Jeghers syndrome (Mehenni H et al. Gut. 2006; 55:984-90; Hearle N et al. Clin. Cancer Res. 2006; 12:3209-15). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		9.9
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 3
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs886039554; hg19: chr19-1220505; COSMIC: COSV58824629; COSMIC: COSV58824629;