rs201787206

chr12-112477722-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1 PP2 BP4_Strong BP6_Very_Strong BS2

The NM_002834.5(PTPN11):c.925A>G(p.Ile309Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,611,852 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:16
• Conservation: PhyloP100: 2.94

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PM1: In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 130 pathogenic changes around while only 9 benign (94%) in NM_002834.5
• PP2: Missense variant where missense usually causes diseases, PTPN11
• BP4: Computational evidence support a benign effect (MetaRNN=0.015743464).
• BP6: Variant 12-112477722-A-G is Benign according to our data. Variant chr12-112477722-A-G is described in ClinVar as [Benign]. Clinvar id is 40536.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-112477722-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.925A>G	p.Ile309Val	missense_variant	8/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.925A>G	p.Ile309Val	missense_variant	8/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000497 AC: 125 AN: 251440 Hom.: 1 AF XY: 0.000412 AC XY: 56 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000212 AC: 310 AN: 1459656 Hom.: 1 Cov.: 32 AF XY: 0.000224 AC XY: 163 AN XY: 726296

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00873

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.000481

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000580 Hom.: 2

Bravo AF: 0.000257

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 10, 2017	p.Ile309Val in exon 8 of PTPN11: This variant is not expected to have clinical s ignificance because it has been identified in 1% (103/10152) of Ashkenazi Jewish chromosomes, including 1 homozygous individual, by the Genome Aggregation Datab ase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201787206). Furthermore, the p.Ile307Val variant has been identified in at least 2 unaffected individuals (Tartaglia 2002, LMM data). ACMG/AMP Criteria applied: BA1, BS2 (Richards 2015) . -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Nov 12, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 27, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2016	Variant summary: The PTPN11 c.925A>G (p.Ile309Val) variant involves the alteration of a conserved nucleotide and affected amino acid (Ile309) is located in the Protein-tyrosine phosphatase(PTP)-like domain. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 50/121802 control chromosomes (1 homozygote) at a frequency of 0.0004105, which is approximately 7 times the estimated maximal expected allele frequency of a pathogenic PTPN11 variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported in NS patients and at least one unaffected parent, suggesting this variant may not be associated with the disease. In addition, one clinical diagnostic laboratory classified this variant as likely benign and provided following description: "this variant has been identified in 3/80 (3.8%) of Ashkenazi-Jewish control chromosomes (Dr. Bruce Gelb, LMM personal communication), suggesting that this variant is a common polymorphism in this population." Taken together, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PTPN11: PP2, BS1 -

Metachondromatosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

RASopathy Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The filtering allele frequency of the c.925A>G (p.Ile309Val) variant in the PTPN11 gene is 0.04% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (46/66736 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -

Noonan syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

LEOPARD syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

PTPN11-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2019

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

Noonan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Sep 30, 2020

The c.925A>G missense variant has a frequency of 0.0004596 (130 of 282,830) in gnomAD v2.1.1 with a maximal allele frequency of 0.01003 (104 of 10,370) in the Ashkenazi Jewish subpopulation including one homozygote (http://gnomad.broadinstitute.org). This is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581; SCV000616415.3). Although five of seven in silico algorithms predict a deleterious effect on the gene or gene product (PP3), these predictions have not been confirmed by functional studies. In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

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. -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
CardioboostCm	Benign	0.025
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.25
Eigen_PC	Benign	0.027
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	-0.48	N;N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.20	N;N;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0050	D;D;.
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.52
MVP		0.98
MPC		0.71
ClinPred		0.056	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.27

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

Other links and lift over

dbSNP: rs201787206; hg19: chr12-112915526; COSMIC: COSV100692935; COSMIC: COSV100692935;