rs397507506
Variant summary
Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_002834.5(PTPN11):c.174C>A(p.Asn58Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N58D) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
PTPN11
NM_002834.5 missense
NM_002834.5 missense
Scores
6
10
4
Clinical Significance
Conservation
PhyloP100: 1.78
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 23 ACMG points.
PS1
Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
PM1
In a domain SH2 1 (size 96) in uniprot entity PTN11_HUMAN there are 61 pathogenic changes around while only 0 benign (100%) in NM_002834.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-112450352-A-G is described in Lovd as [Likely_pathogenic].
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, 0.946
PP5
Variant 12-112450354-C-A is Pathogenic according to our data. Variant chr12-112450354-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 40488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450354-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTPN11 | NM_002834.5 | c.174C>A | p.Asn58Lys | missense_variant | 3/16 | ENST00000351677.7 | NP_002825.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PTPN11 | ENST00000351677.7 | c.174C>A | p.Asn58Lys | missense_variant | 3/16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | c.174C>A | p.Asn58Lys | missense_variant | 3/15 | 5 | ENSP00000489597.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Multiple pathogenic missense variants at this residue (p.N58D, p.N58Y, p.N58H) have been reported in association with Noonan spectrum disorders; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34184824, 26633542, 29212898, 28911804, 30050098, 29907801, 11992261, 9491886, 16053901, 29493581, 34782754) - |
| Pathogenic, no assertion criteria provided | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 15, 2015 | - - |
Noonan syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Noonan syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 28, 2021 | The p.Asn58Lys (c.174C>A) variant in PTPN11 has been reported in at least six individuals with Noonan syndrome and segregated with disease in one affected family member (Chan 2006, Miller 2017 PMID: 29212898, Sublett 2017 PMID: 28911804, D'Amico 2021 PMID: 33811550, LMM data). It has also been reported in one individual with multiple congenital anomalies (Retterer 2015 PMID:26633542). It was absent from large population studies, but has been reported in ClinVar (Variation ID 40488). Another variant resulting in the same amino acid change (c.174C>G) and two additional variants involving this codon (p.Asn58Asp and p.Asn58His) have been identified in individuals with Noonan syndrome and are classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP Criteria applied: PS1, PS4, PM5_Strong, PM2_Supporting. - |
Noonan syndrome 3 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 25, 2016 | Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a medium size and polar Asparagine (N) with a large size and basic Lysine (K). 4/4 in silico tools predict the variant to be disease causing. It is absent from the large and broad cohorts of the ExAC project while it was found in several NS patients either as a de novo or as a familiar mutation suggesting pathogenicity. Variants affecting the same amino acid, Asn58His and Asn58Asp, Asn58Tyr have been reported by our laboratory in the pathogenic spectrum suggesting the Asn58 residue to be a mutational hotspot and further supporting a casual outcome for the variant. Furthermore, clinical diagnostic centers classify variant as Pathogenic via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Pathogenic. - |
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2+PS1+PM5_Strong+PS4_Moderate+PP2 - |
Noonan syndrome and Noonan-related syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 01, 2018 | - - |
RASopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 11, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12634870, 15001945, 15956085, 16263833, 16358218, 19125092, 20954246, 21204800, 22190897, 23321623, 23624134, 23756559, 25914815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 40488). A different variant (c.174C>G) giving rise to the same protein effect has been determined to be pathogenic (PMID: 12634870, 15001945, 15956085, 16263833, 16358218, 19125092, 20954246, 21204800, 22190897, 23321623, 23624134, 23756559, 25914815). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58Lys). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N;.;N
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.;.
REVEL
Uncertain
Sift
Uncertain
D;D;.;.
Sift4G
Benign
T;T;.;T
Polyphen
D;D;.;.
Vest4
MutPred
Gain of methylation at N58 (P = 0.0017);Gain of methylation at N58 (P = 0.0017);Gain of methylation at N58 (P = 0.0017);Gain of methylation at N58 (P = 0.0017);
MVP
MPC
2.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at