12-112453279-G-T

Variant names:

• chr12-112453279-G-T
• rs397507520
• NM_002834.5:c.417G>T

Variant summary

Our verdict is Pathogenic. The variant received 25 ACMG points: 25P and 0B. PS1_Very_Strong PM2 PM5 PP2 PP3_Strong PP5_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 Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E139G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.63
• Publications: 63 publications found

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 Gene-Disease associations (from GenCC):

• LEOPARD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000305447 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 25 ACMG points.

• PS1: Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112453278-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2095543.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 Costello syndrome, Noonan syndrome 1, Noonan syndrome, LEOPARD syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, metachondromatosis.
• 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 VariationId is 40512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	NM_002834.5	MANE Select	c.417G>T	p.Glu139Asp	missense	Exon 4 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.417G>T	p.Glu139Asp	missense	Exon 4 of 16	NP_001317366.1
	PTPN11	NM_001374625.1		c.414G>T	p.Glu138Asp	missense	Exon 4 of 16	NP_001361554.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.417G>T	p.Glu139Asp	missense	Exon 4 of 16	ENSP00000340944.3
	PTPN11	ENST00000635625.1	TSL:5	c.417G>T	p.Glu139Asp	missense	Exon 4 of 15	ENSP00000489597.1
	PTPN11	ENST00000392597.5	TSL:1	c.417G>T	p.Glu139Asp	missense	Exon 4 of 11	ENSP00000376376.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

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)

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Noonan syndrome 1 Pathogenic:2

Jun 13, 2018

Institute of Human Genetics Munich, TUM University Hospital

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.1	L
PhyloP100		3.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.78
MutPred		0.90		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.98
MPC		1.8
ClinPred		0.96	D
GERP RS		4.5
PromoterAI		0.0094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.71
gMVP		0.61
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397507520; hg19: chr12-112891083; COSMIC: COSV61007093; COSMIC: COSV61007093;