12-112486482-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

This summary comes from the ClinGen Evidence Repository: The c.1232C>T (p.Thr411Met) variant PTPN11 is present in 0.003% (3/113264) non-Finnish European alleles in gnomAD. The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). Observed cases from laboratories and publications lack sufficient clinical phenotypic information to support or refute pathogenicity (Institut Universitaire d'Hématologie internal data; Institute of Human Genetics, University Hospital Magdeburg, Germany internal data; PMID:15384080). In summary, the clinical significance of the p.Thr411Met variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA256755/MONDO:0021060/004

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:3U:5

Conservation

PhyloP100: 7.54

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.1232C>T	p.Thr411Met	missense_variant	Exon 11 of 16	ENST00000351677.7	NP_002825.3	Q06124-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PTPN11	ENST00000351677.7 link	c.1232C>T	p.Thr411Met	missense_variant	Exon 11 of 16	1	NM_002834.5	ENSP00000340944.3	Q06124-2
PTPN11	ENST00000635625.1 link	c.1244C>T	p.Thr415Met	missense_variant	Exon 11 of 15	5		ENSP00000489597.1	Q06124-1
PTPN11	ENST00000635652.1 link	c.245C>T	p.Thr82Met	missense_variant	Exon 3 of 5	3		ENSP00000489541.1	A0A0U1RRI0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250954

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461448

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000969

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Noonan syndrome 1

Pathogenic:2

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Uncertain:2

Sep 16, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy

Uncertain:2

Dec 05, 2019

ClinGen RASopathy Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1232C>T (p.Thr411Met) variant PTPN11 is present in 0.003% (3/113264) non-Finnish European alleles in gnomAD. The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Observed cases from laboratories and publications lack sufficient clinical phenotypic information to support or refute pathogenicity (Institut Universitaire d'Hematologie internal data; Institute of Human Genetics, University Hospital Magdeburg, Germany internal data; PMID:15384080). In summary, the clinical significance of the p.Thr411Met variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2. -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 411 of the PTPN11 protein (p.Thr411Met). This variant is present in population databases (rs121918467, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 15384080). ClinVar contains an entry for this variant (Variation ID: 13341). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PTPN11 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Acute megakaryoblastic leukemia in down syndrome

Pathogenic:1

Sep 01, 2020

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Jun 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T411M variant (also known as c.1232C>T), located in coding exon 11 of the PTPN11 gene, results from a C to T substitution at nucleotide position 1232. The threonine at codon 411 is replaced by methionine, an amino acid with similar properties. In one study, this alteration was detected in three individuals from one family: one who met diagnostic criteria for Noonan syndrome and two who showed some symptoms, but did not meet formal diagnostic criteria. In addition, this alteration was not detected in two unaffected individuals from the same family (Bertola DR et al. Am. J. Med. Genet. A, 2004 Nov;130A:378-83). This alteration has also been noted in a stillbirth cohort (Stanley KE et al. N Engl J Med, 2020 Sep;383:1107-1116). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

CardioboostCm

Benign

0.029

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

.;.;D;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;T;T;T

M_CAP

Benign

0.082

MetaRNN

Uncertain

0.69

D;D;D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.3

.;.;L;.

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.1

N;N;.;.

REVEL

Uncertain

0.63

Sift

Benign

0.10

T;T;.;.

Sift4G

Benign

0.097

T;T;T;T

Polyphen

1.0

D;P;.;.

Vest4

0.49

MVP

0.88

MPC

0.94

ClinPred

0.62

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.78

gMVP

0.62

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