12-112453279-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.417G>T(p.Glu139Asp) variant causes a missense change. 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 the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.

Frequency

Genomes: not found (cov: 32)

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.63

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]

PTPN11 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 21 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 strand (size 5) in uniprot entity PTN11_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002834.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the PTPN11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.1293 (above the threshold of 3.09). Trascript score misZ: 4.9438 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.942

PP5

Variant 12-112453279-G-T is Pathogenic according to our data. Variant chr12-112453279-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 40512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112453279-G-T is described in Lovd as [Likely_pathogenic]. Variant chr12-112453279-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.417G>T	p.Glu139Asp	missense_variant	Exon 4 of 16	ENST00000351677.7	NP_002825.3	Q06124-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 link	c.417G>T	p.Glu139Asp	missense_variant	Exon 4 of 16	1	NM_002834.5	ENSP00000340944.3		Q06124-2
PTPN11	ENST00000635625.1 link	c.417G>T	p.Glu139Asp	missense_variant	Exon 4 of 15	5		ENSP00000489597.1		Q06124-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with features of PTPN11-related RASopathy in the literature and tested at GeneDx (PMID: 11992261); Published functional studies demonstrate a damaging effect (PMID: 20308328, 18372317); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22135187, 18372317, 23584145, 20308328, 24628801, 30355600, 21407260, 11992261, 22315187, 33318624) -

Noonan syndrome 1

Pathogenic:2

Jun 13, 2018

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Dec 21, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia

Pathogenic:1

Jan 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu139Asp (c.417G>T) variant in PTPN11 has been identified in 3 individua ls with Noonan syndrome (Tartaglia 2002, LMM unpublished data). It has not been identified in large population studies. In addition, another nucleotide change (c.417G>C) that results in the same amino acid change has also been reported in at least 10 individuals with Noonan syndrome, 1 individual with Noonan syndrome and acute lymphoblastic leukemia (ALL), 1 individual with Juvenile myelomonocyti c leukemia (JMML), and 1 individual with Noonan syndrome that developed ALL and JMML (Musante 2002, Loh 2004, Bertola 2006, Chan 2006, Hung 2007, Karow 2007, Ko 2008, Derbent 2010, Jongmans 2011, Pauli 2012, Timeus 2013). This variant has b een reported to show both familial segregation and to have occurred de novo (Jon gmans 2005, Houweling 2010). In summary, this variant meets our criteria to be c lassified as pathogenic (http://www.partners.org/personalizedmedicine/LMM). -

RASopathy

Pathogenic:1

Jul 22, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change affects PTPN11 protein function (PMID: 18372317, 23584145, 20308328). This sequence change replaces glutamic acid with aspartic acid at codon 139 of the PTPN11 protein (p.Glu139Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11992261, 16358218, 19020799, 17339163). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40512). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostCm

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

.;.;.;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.67

T;T;T;T

M_CAP

Uncertain

0.089

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.1

L;L;.;L

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.4

N;D;.;.

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0090

D;D;.;.

Sift4G

Uncertain

0.015

D;D;.;D

Polyphen

0.99

D;D;.;.

Vest4

0.78

MutPred

0.90

Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);

MVP

0.98

MPC

1.8

ClinPred

0.96

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.71

gMVP

0.61

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over