rs370207155
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000455.5(STK11):c.1185A>G(p.Thr395=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000733 in 1,608,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T395T) has been classified as Likely benign.
Frequency
Consequence
NM_000455.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STK11 | NM_000455.5 | c.1185A>G | p.Thr395= | synonymous_variant | 9/10 | ENST00000326873.12 | |
STK11 | NR_176325.1 | n.2452A>G | non_coding_transcript_exon_variant | 10/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.1185A>G | p.Thr395= | synonymous_variant | 9/10 | 1 | NM_000455.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000434 AC: 66AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000481 AC: 113AN: 235154Hom.: 0 AF XY: 0.000611 AC XY: 79AN XY: 129226
GnomAD4 exome AF: 0.000764 AC: 1112AN: 1455858Hom.: 0 Cov.: 31 AF XY: 0.000750 AC XY: 543AN XY: 723822
GnomAD4 genome ? AF: 0.000434 AC: 66AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32AN XY: 74380
ClinVar
Submissions by phenotype
Peutz-Jeghers syndrome Uncertain:1Benign:5
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 09, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Jul 12, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 14, 2023 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 13, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 12, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | STK11: BP4, BP7 - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 09, 2017 | Variant summary: The c.1185A>G (p.Thr395=) in STK11 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.0004106 (31/75494 chrs tested), predominantly in individuals of European origin (0.0006144; 26/42320 chrs). The observed frequency exceeds the maximum expected allele frequency for a pathogenic variant in this gene (0.0000156), suggesting that it is a benign polymorphism. The variant was identified in at least 1 HBOC pt without strong evidence for causality. The variant of interest has been cited as Benign by multiple reputable databases/clinical laboratories. Taking together, the variant was classified as Benign. - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 18, 2014 | 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 31, 2015 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 13, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Sep 13, 2017 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 06, 2023 | - - |
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 p.Thr395= variant was identified in 1 of 66 proband chromosomes (frequency: 0.02) from Australian individuals or families with Peutz–Jeghers Syndrome (Chow 2006). The variant was also identified in dbSNP (ID: rs370207155) “With other allele”, ClinVar (classified benign by Invitae, GeneDx and likely benign by Ambry Genetics, Prevention Genetics and Counsyl), Clinvitae (3x), Zhejiang Colon Cancer Database (1x), but was not identified in Cosmic, LOVD 3.0, and Insight Hereditary Tumors Database. The variant was identified in control databases in 125 of 263502 chromosomes at a frequency of 0.0005 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 4 of 22240 chromosomes (frequency: 0.0002), Other in 2 of 6164 chromosomes (frequency: 0.0003), Latino in 8 of 33706 chromosomes (frequency: 0.0002), European Non-Finnish in 79 of 119338 chromosomes (frequency: 0.0006),and European Finnish in 32 of 24350 chromosomes (frequency: 0.001). The p.Thr395= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. 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