rs727503381
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP2PP3PP5_Very_Strong
The ENST00000351677.7(PTPN11):c.598A>T(p.Asn200Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
PTPN11
ENST00000351677.7 missense
ENST00000351677.7 missense
Scores
8
9
3
Clinical Significance
Conservation
PhyloP100: 8.92
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 Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTPN11. . Gene score misZ 3.1293 (greater than the threshold 3.09). Trascript score misZ 4.9438 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome and Noonan-related syndrome, Noonan syndrome with multiple lentigines, metachondromatosis, Noonan syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome 1, Costello syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.836
PP5
Variant 12-112454636-A-T is Pathogenic according to our data. Variant chr12-112454636-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTPN11 | NM_002834.5 | c.598A>T | p.Asn200Tyr | missense_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.598A>T | p.Asn200Tyr | missense_variant | 5/16 | 1 | NM_002834.5 | ENSP00000340944 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461588Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727096
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74318
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2023 | Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33771761, 24225993, 28991257, 33042901, 32368696, 30417923) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Noonan syndrome Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 08, 2015 | The p.Asn200Tyr variant in PTPN11 has been reported in one individual with Noona n syndrome and multiple giant cell lesions and in her mother with Noonan syndrom e without multiple giant cell lesions (Carapito 2014). This variant was reported to have occurred de novo in the proband's mother. It has also been identified i n two individuals with clinical features of Noonan syndrome by our laboratory. T his variant was absent from large population studies. In summary, this variant m eets our criteria to be classified as pathogenic (http://www.partners.org/person alizedmedicine/LMM). - |
PTPN11-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 20, 2024 | The PTPN11 c.598A>T variant is predicted to result in the amino acid substitution p.Asn200Tyr. This variant has been reported, often arising de novo, in individuals with Noonan syndrome (see for examples: Carapito et al. 2014. PubMed ID: 24225993; Ferriero et al. 2020. PubMed ID: 33042901; Dufke et al. 2022. PubMed ID: 35574990). This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD; however, the total allele number for this dataset is relatively small and larger updated datasets report a highest allele frequency of of 0.002% (https://gnomad.broadinstitute.org/variant/12-112454636-A-T?dataset=gnomad_r4). Given the evidence, we interpret this variant as pathogenic. - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 05, 2022 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 164998). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 24225993, 30417923). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs727503381, gnomAD 0.1%). This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 200 of the PTPN11 protein (p.Asn200Tyr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L;.;L
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.;.
REVEL
Pathogenic
Sift
Benign
T;T;.;.
Sift4G
Uncertain
D;D;.;D
Polyphen
P;P;.;.
Vest4
MutPred
Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP
MPC
2.0
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at