rs1060499956

Positions:

• chr19-1219416-G-A
• chr19-1219416-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000455.5(STK11):​c.464+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,426,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: STK11 NM_000455.5 splice_region, intron
• Scores: Splicing: ADA: 0.00008536
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 1.31

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-1219416-G-A is Benign according to our data. Variant chr19-1219416-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403768.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.464+3G>A		splice_region_variant, intron_variant		ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.464+3G>A		splice_region_variant, intron_variant			NP_001394184.1
STK11	NR_176325.1	n.1731+3G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.464+3G>A		splice_region_variant, intron_variant		1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.464+3G>A		splice_region_variant, intron_variant				ENSP00000498804.1
STK11	ENST00000585748.3	c.92+3G>A		splice_region_variant, intron_variant		3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1426538 Hom.: 0 Cov.: 52 AF XY: 0.00 AC XY: 0 AN XY: 706284

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: 0.00000365

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 04, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 20, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2023	This sequence change falls in intron 3 of the STK11 gene. It does not directly change the encoded amino acid sequence of the STK11 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). 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: 403768). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 12, 2023	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 01, 2023	The c.464+3G>A intronic variant results from a G to A substitution 3 nucleotides after coding exon 3 in the STK11 gene. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 08, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.1
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000085
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs1060499956; hg19: chr19-1219415;