chr12-112453254-A-G

Position:

chr12-112453254-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP5BS1

This summary comes from the ClinGen Evidence Repository: The c.392A>G (p.Lys131Arg) variant in the PTPN11 gene has been identified in a patient with an alternate molecular basis of disease (BP5; Laboratory for Molecular Medicine internal data; VCV000013351.2, GeneDx internal data; VCV000013351.2). The filtering allele frequency of p.Lys131Arg variant is 0.042% for East Asian alleles in the gnomAD database (14/19952 with 95% CI), which is a high enough frequency to be considered strong evidence for the variant being benign by the ClinGen RASopathy Expert Panel (BS1). 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 not met due to case level data indicative of benign). This variant was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2 not met; Université Paris Diderot internal data). The ClinGen RASopathy Expert Panel has classified the p.Lys131Arg variant as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA134665/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:9O:1

Conservation

PhyloP100: 9.32

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 Likely_benign. Variant got -5 ACMG points.

BP5

BS1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5 linkuse as main transcript	c.392A>G	p.Lys131Arg	missense_variant	4/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7 linkuse as main transcript	c.392A>G	p.Lys131Arg	missense_variant	4/16	1	NM_002834.5	A1	Q06124-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251376

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000652

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461164

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2011	The Lys131Arg variant in PTPN11 has been reported in the literature in one Chine se individual with clinical features of Noonan syndrome (Chan 2006). This varian t was identified in that individual's mother; however clinical features for the mother were not provided. In addition, this variant has been detected by our lab oratory in one Asian proband who also has a pathogenic MEK1 variant. The Lys131 residue is highly conserved across mammals and lower species and computational a nalyses (PolyPhen2, SIFT, AlignGVGD) suggest that the Lys131Arg variant may impa ct the normal function of PTPN11. Given this information, we are unable to make a conclusive determination as to whether this variant is responsible for the cli nical features observed in this individual. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2024	Variant summary: PTPN11 c.392A>G (p.Lys131Arg) results in a conservative amino acid change located in the SH2 domain 2 (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251376 control chromosomes, predominantly at a frequency of 0.00065 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome And Related Conditions phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.392A>G, has been reported in the literature in Chinese individuals, who were affected with Noonan Syndrome and Related Conditions (Chan_2006, Yu_2019), however without providing supportive evidence for causality. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. In addition, the variant was also reported in healthy individuals of East Asian ancestry (Bodian_2014). ClinVar contains an entry for this variant (Variation ID: 44607). Based on the evidence outlined above, the variant was classified as likely benign. -

Noonan syndrome

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Mar 08, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2020	This variant is associated with the following publications: (PMID: 30896080, 24728327) -

RASopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Aug 19, 2019	The c.392A>G (p.Lys131Arg) variant in the PTPN11 gene has been identified in a patient with an alternate molecular basis of disease (BP5; Laboratory for Molecular Medicine internal data; VCV000013351.2, GeneDx internal data; VCV000013351.2). The filtering allele frequency of p.Lys131Arg variant is 0.042% for East Asian alleles in the gnomAD database (14/19952 with 95% CI), which is a high enough frequency to be considered strong evidence for the variant being benign by the ClinGen RASopathy Expert Panel (BS1). 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 not met due to case level data indicative of benign). This variant was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2 not met; Universite Paris Diderot internal data). The ClinGen RASopathy Expert Panel has classified the p.Lys131Arg variant as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5. -

Noonan syndrome and Noonan-related syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

PTPN11-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

CardioboostCm

Benign

0.017

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

.;.;.;D

Eigen

Benign

0.043

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

T;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

0.70

N;N;.;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.3

N;N;.;.

REVEL

Uncertain

0.31

Sift

Benign

0.25

T;T;.;.

Sift4G

Benign

0.62

T;T;.;T

Polyphen

0.0080

B;B;.;.

Vest4

0.44

MutPred

0.38

Loss of ubiquitination at K131 (P = 0.0103);Loss of ubiquitination at K131 (P = 0.0103);Loss of ubiquitination at K131 (P = 0.0103);Loss of ubiquitination at K131 (P = 0.0103);

MVP

0.82

MPC

1.7

ClinPred

0.12

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.63

gMVP

0.54

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