rs727503381

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

Scores

8
9
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 8.92
Variant links:
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]

Genome browser will be placed here

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
PTPN11NM_002834.5 linkuse as main transcriptc.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
PTPN11ENST00000351677.7 linkuse as main transcriptc.598A>T p.Asn200Tyr missense_variant 5/161 NM_002834.5 ENSP00000340944 A1Q06124-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152156
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461588
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727096
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152156
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

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 submitterclinical testingGeneDxFeb 10, 2023Missense 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 submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Noonan syndrome Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingService de Génétique Moléculaire, Hôpital Robert Debré-- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 08, 2015The 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 providedclinical testingPreventionGenetics, part of Exact SciencesJun 20, 2024The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 05, 2022For 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
CardioboostCm
Uncertain
0.11
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.83
.;.;.;D
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Pathogenic
0.84
D;D;D;D
MetaSVM
Uncertain
-0.085
T
MutationAssessor
Benign
1.6
L;L;.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-4.6
D;D;.;.
REVEL
Pathogenic
0.95
Sift
Benign
0.080
T;T;.;.
Sift4G
Uncertain
0.0050
D;D;.;D
Polyphen
0.84
P;P;.;.
Vest4
0.92
MutPred
0.48
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
0.90
MPC
2.0
ClinPred
0.98
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.83
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727503381; hg19: chr12-112892440; API