chr12-112454596-G-T
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.558G>T (p.Arg186=) variant in the PTPN11 gene is 0.231% (49/16504) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA181422/MONDO:0021060/004
Frequency
Genomes: 𝑓 0.00018 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 2 hom. )
Consequence
PTPN11
NM_002834.5 synonymous
NM_002834.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.880
Genes affected
PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BA1
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTPN11 | NM_002834.5 | c.558G>T | p.Arg186Arg | synonymous_variant | 5/16 | ENST00000351677.7 | NP_002825.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PTPN11 | ENST00000351677.7 | c.558G>T | p.Arg186Arg | synonymous_variant | 5/16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | c.558G>T | p.Arg186Arg | synonymous_variant | 5/15 | 5 | ENSP00000489597.1 |
Frequencies
GnomAD3 genomes 0.000177 AC: 27AN: 152154Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000474 AC: 119AN: 251082Hom.: 0 AF XY: 0.000626 AC XY: 85AN XY: 135698
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GnomAD4 exome AF: 0.000268 AC: 391AN: 1461480Hom.: 2 Cov.: 31 AF XY: 0.000366 AC XY: 266AN XY: 727060
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GnomAD4 genome 0.000184 AC: 28AN: 152270Hom.: 1 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74452
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ClinVar
Significance: Benign
Submissions summary: Benign:16
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:5
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2015 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | p.Arg186Arg in Exon 05 of PTPN11: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence. It has been identified in 1/3738 African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS;). - |
| Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 15, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 18, 2019 | - - |
not provided Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | PTPN11: BP4, BP7, BS1 - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 31, 2016 | Variant summary: The PTPN11 c.558G>T (p.Arg186Arg) variant causes a synonymous change involving a non-conserved nucleotide with 3/5 splice prediction tools predict no significant impact on normal splicing and no alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 60/121366 (1/2022, 1 homozygote), predominantly observed in the South Asian cohort, 49/16504 (1/336, 1 homozygote), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PTPN11 variant of 1/16000. Therefore, suggesting the variant is a common polymorphism found in population(s) of South Asian origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. However, multiple clinical diagnostic laboratories/databases cite the variant as "likely benign." Therefore, the variant of interest has been classified as Benign. - |
RASopathy Benign:2
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
| Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 18, 2017 | The filtering allele frequency of the c.558G>T (p.Arg186=) variant in the PTPN11 gene is 0.231% (49/16504) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) - |
LEOPARD syndrome 1 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Noonan syndrome 1 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Metachondromatosis Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Juvenile myelomonocytic leukemia Benign:1
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 25, 2022 | - - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 03, 2017 | 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. - |
Noonan syndrome and Noonan-related syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 01, 2020 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at