rs587780009
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000455.5(STK11):c.465-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,598,454 control chromosomes in the GnomAD database, including 1 homozygotes. 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
Consequence
NM_000455.5 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STK11 | NM_000455.5 | c.465-4G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000326873.12 | |||
STK11 | NM_001407255.1 | c.465-4G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
STK11 | NR_176325.1 | n.1732-4G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.465-4G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000455.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000850 AC: 19AN: 223438Hom.: 0 AF XY: 0.0000988 AC XY: 12AN XY: 121414
GnomAD4 exome AF: 0.0000615 AC: 89AN: 1446234Hom.: 1 Cov.: 32 AF XY: 0.0000794 AC XY: 57AN XY: 718004
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
Peutz-Jeghers syndrome Uncertain:2Benign:4
Uncertain significance, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 26, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 14, 2023 | This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 16, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 12, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Mar 22, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 22, 2015 | - - |
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 15, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is a splice variant in intron 3 of STK11 (10 total exons). The variant has been reported in one individual with Peutz Jeghers (Aretz 2005). This variant is has a Max MAF of 0.07% in ExAC (7 South Asian alleles) and 0.04% in gnomAD (12 South Asian alleles). Classified as Likely benign by 3 submitters (GeneDx, Ambry, Invitae) and VUS by Pathway Genomics. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 13, 2023 | Variant summary: STK11 c.465-4G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing. The variant allele was found at a frequency of 8.5e-05 in 223438 control chromosomes, predominantly at a frequency of 0.0004 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 64 fold of the estimated maximal estimated allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.465-4G>A has been reported in the literature in one individual affected with Peutz-Jeghers Syndrome (Aretz_2005), however authors are unclear about the possible splice impact. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified as Benign (n=1), Likely Benign (n=7) and VUS (n=5). Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 01, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 22, 2021 | This variant is associated with the following publications: (PMID: 16287113, 28873162) - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 17, 2023 | - - |
Breast carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The STK11 c.465-4G>A variant was identified in 1 of 142 proband chromosomes (frequency: 0.007) from individuals or families with Peutz-Jeghers syndrome (Aretz 2005). The variant was also identified in the following databases: dbSNP (ID: rs587780009) as "With other allele", ClinVar (2x uncertain significance, 3x likely benign), Clinvitae, and the Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic, MutDB, LOVD 3.0, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 19 of 220968 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include other in 1 of 5028 chromosomes (freq: 0.0002), Latino in 4 of 31136 chromosomes (freq: 0.0001), European in 2 of 99398 chromosomes (freq: 0.00002), Ashkenazi Jewish in 1 of 9228 chromosomes (freq: 0.0001), and South Asian in 11 of 27928 chromosomes (freq: 0.0004). The variant was not observed in the African, East Asian, or Finnish populations. The identification of this variant together with a co-occurring pathogenic variant in the PALB2 gene (c.661_662delinsTA, p.Val221X) by our laboratory in one individual with breast cancer increases the likelihood this variant does not have clinical significance. The c.465-4G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions nor at positions -3 and -5 to -12 which are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at