12-112450361-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_002834.5(PTPN11):​c.181G>T​(p.Asp61Tyr) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D61G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PTPN11
NM_002834.5 missense

Scores

16
2
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 9.99
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a strand (size 2) in uniprot entity PTN11_HUMAN there are 16 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 chr12-112450362-A-G is described in Lovd as [Likely_pathogenic].
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, 0.947
PP5
Variant 12-112450361-G-T is Pathogenic according to our data. Variant chr12-112450361-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228392.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=4}. Variant chr12-112450361-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTPN11NM_002834.5 linkc.181G>T p.Asp61Tyr missense_variant Exon 3 of 16 ENST00000351677.7 NP_002825.3 Q06124-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTPN11ENST00000351677.7 linkc.181G>T p.Asp61Tyr missense_variant Exon 3 of 16 1 NM_002834.5 ENSP00000340944.3 Q06124-2
PTPN11ENST00000635625.1 linkc.181G>T p.Asp61Tyr missense_variant Exon 3 of 15 5 ENSP00000489597.1 Q06124-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Dec 28, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP2, PP3, PM1, PM2, PM5, PS3, PS4 -

Jul 01, 2017
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Noonan syndrome 1 Pathogenic:1Uncertain:1
Sep 09, 2024
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The reported PTPN11 mutation is somatic. PTPN11 is one of the most commonly altered genes in juvenile myelomonocytic leukemia (JMML) and its presence strongly supports a diagnosis of JMML. The PTPN11D61Y is possible germline mutation . -

Apr 04, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Juvenile myelomonocytic leukemia Pathogenic:1
Feb 06, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Asp61Tyr in PTPN11 has been previously reported as a somatic variant in at least 30 sporadic cases of JMML, 10 sporadic cases of other hematological malig nancies, and 1 child with neuroblastoma (Tartaglia 2003, Loh 2004, Tartaglia 200 4, Bentires-Alj 2004, Kratz 2005, Tartaglia 2006, Gelsi-Boyer 2008, Paulsson 200 8, Silva 2009, Yoshida 2009, Pugh 2013, Sakaguchi 2013, Strullu 2014) and was ab sent from large population studies. In vitro and in-vivo studies using mouse mod els have shown strong evidence that this variant affects the protein (Tarataglia 2003, Loh 2004, Chan 2005, Chan 2009, Yang 2010). Other variants at this positi on (p.Asp61Gly, p.Asp61Ala, p.Asp61Asn, p.Asp61His, p.Asp61Val) were also report ed in multiple patients with Noonan syndrome and/or hematological malignancies ( Tartaglia 2005, Kratz 2005, Bertola 2006, Sakaguchi 2013, Strullu 2014). In summ ary, this variant meets our criteria to be classified as pathogenic for JMML (ww w.partners.org/personalizedmedicine/lmm). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
CardioboostCm
Uncertain
0.81
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
.;.;.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.7
L;L;.;L
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-7.4
D;D;.;.
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D;.;.
Sift4G
Pathogenic
0.0010
D;D;.;D
Polyphen
1.0
D;D;.;.
Vest4
0.98
MutPred
0.82
Loss of phosphorylation at Y63 (P = 0.0746);Loss of phosphorylation at Y63 (P = 0.0746);Loss of phosphorylation at Y63 (P = 0.0746);Loss of phosphorylation at Y63 (P = 0.0746);
MVP
1.0
MPC
2.1
ClinPred
1.0
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.84

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: rs397507510; hg19: chr12-112888165; COSMIC: COSV61004841; COSMIC: COSV61004841; API