12-112450353-A-G

Position:

chr12-112450353-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM5PP2PP5BS2_Supporting

The NM_002834.5(PTPN11):c.173A>G(p.Asn58Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000639 in 1,613,116 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N58D) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:8

Conservation

PhyloP100: 9.31

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 5 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002834.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-112450352-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 40487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTPN11. . Gene score misZ 3.1293 (greater than the threshold 3.09). Trascript score misZ 4.9438 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome and Noonan-related syndrome, Noonan syndrome with multiple lentigines, metachondromatosis, Noonan syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome 1, Costello syndrome.

PP5

Variant 12-112450353-A-G is Pathogenic according to our data. Variant chr12-112450353-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372483.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=4}.

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5 linkuse as main transcript	c.173A>G	p.Asn58Ser	missense_variant	3/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7 linkuse as main transcript	c.173A>G	p.Asn58Ser	missense_variant	3/16	1	NM_002834.5	A1	Q06124-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152174

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

251000

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135636

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:

0.0000794

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000671

AC:

AN:

1460942

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726830

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000819

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:4

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PTPN11: PM1, PM5, PP3, PP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2023	Observed as a somatic variant in a lung cancer cell line (Bentires-Alj et al., 2004) and as a germline variant in an individual with childhood acute lymphoblastic leukemia (Case et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 25695693, 26214590, 15604238, 18701506, 23825065, 23957426, 24480804, 20579941, 27168466, 30050098, 11992261, 9491886, 16053901, 29493581, 35385746, 29625052, 29907801) -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PTPN11 p.Asn58Ser variant was identified in dbSNP (ID: rs751437780), ClinVar (classified as a VUS by Invitae, GeneDx and Integrated Genetics/Laboratory Corporation of America) and Cosmic (FATHMM prediction of pathogenic; score=0.99). The variant was also identified in control databases in 10 of 282404 chromosomes at a frequency of 0.000035 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 10 of 128726 chromosomes (freq: 0.000078), but not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The N58S variant has been identified somatically in a metastatic breast tumor (Goswami_2015_PMID:25695693). Germline mutations at the same residue (N58H, N58D and N58K) have been identified in patients with Noonan syndrome and LEOPARD syndrome, and the N58Y somatic mutation was identified in patients with hematologic malignancies (Coromilas_2015_PMID:25914815; Tartaglia_2006_PMID:16358218). The p.Asn58 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 02, 2018	Variant summary: PTPN11 c.173A>G (p.Asn58Ser) results in a conservative amino acid change located in the first SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.26 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome and Related Conditions phenotype (6.3e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.173A>G in individuals affected with Noonan Syndrome and Related Conditions has been reported. However, c.173A>G (p.Asn58Ser) has been observed previously as a somatic mutation in a lung cancer cell line (Bentires-Alj 2004) and was reported in association with childhood acute lymphoblastic leukemia in an individual as a somatic and germline variant (Case 2008). Other missense variants affecting the same amino acid position have been reported in Noonan syndrome (N58K, N58D, N58K; Kratz 2005, Tartaglia 2006) and childhood acute leukemia (N58Y, somatic, Tartaglia 2004); these reports might indicate the importance of this residue for protein function. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. The c.173A>G has been identified in an internal sample undergoing genetic testing due to abnormal US findings and was confirmed to be is maternally inherited. However, mother was not evaluated by clinical geneticist and, therefore association of N58S with NS remains to be established (internal data). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 22, 2019	- -

RASopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 58 of the PTPN11 protein (p.Asn58Ser). This variant is present in population databases (rs751437780, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of PTPN11-related conditions (PMID: 29907801). ClinVar contains an entry for this variant (Variation ID: 372483). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15956085, 16263833, 16804314, 19125092, 25914815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

PTPN11-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2024

The PTPN11 c.173A>G variant is predicted to result in the amino acid substitution p.Asn58Ser. This variant has been reported in a fetus with increased nuchal translucency (Table S2, Leach et al. 2019. PubMed ID: 29907801). In ClinVar, this variant has conflicting interpretations of pathogenicity of uncertain and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/372483/). However, this variant has also been reported in 10 out of ~282,000 alleles in the gnomAD v2 database (as displayed in the table above). In addition, in gnomAD v4 (available only on GRCh38), this variant is reported in 103 out of ~1,613,000 alleles (https://gnomad.broadinstitute.org/variant/12-112450353-A-G?dataset=gnomad_r4). Alternate missense variants affecting this amino acid (p.Asn58His, p.Asn58Asp, p.Asn58Lys) have been reported as pathogenic (ClinVar IDs: 40486, 40487, 40488, 40489). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2019

The p.N58S variant (also known as c.173A>G), located in coding exon 3 of the PTPN11 gene, results from an A to G substitution at nucleotide position 173. The asparagine at codon 58 is replaced by serine, an amino acid with highly similar properties. Alternate amino acid substitutions at this position, p.N58H, p.N58D, and p.N58K, have been reported in individuals with Noonan syndrome (Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). 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

Pathogenic

0.74

CardioboostCm

Benign

0.039

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

.;.;.;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.73

D;D;D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

0.96

L;L;.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.5

D;D;.;.

REVEL

Uncertain

0.61

Sift

Uncertain

0.020

D;D;.;.

Sift4G

Benign

0.12

T;T;.;T

Polyphen

0.97

D;P;.;.

Vest4

0.90

MVP

0.86

MPC

1.6

ClinPred

0.54

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.58

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