chr12-112450394-G-A

Position:

• chr12-112450394-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002834.5(PTPN11):​c.214G>A​(p.Ala72Thr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A72D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.99

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a domain SH2 1 (size 96) in uniprot entity PTN11_HUMAN there are 61 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 chr12-112450395-C-A is described in Lovd as [Likely_pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• PP5: Variant 12-112450394-G-A is Pathogenic according to our data. Variant chr12-112450394-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450394-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.214G>A	p.Ala72Thr	missense_variant	3/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.214G>A	p.Ala72Thr	missense_variant	3/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.214G>A	p.Ala72Thr	missense_variant	3/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2023	Frequently observed as a somatic variant in patients with juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), and/or myelodysplastic syndrome (MDS) (Tartaglia et al., 2003; Kratz et al., 2005; Tartaglia et al., 2006; Christiansen et al., 2007; Hou et al., 2008; Park et al., 2012; Stasik et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17972951, 12634870, 16518851, 21901340, 12717436, 14982869, 16358218, 17330262, 17353900, 28098151, 11992261, 9491886, 16053901, 29493581, 32786180, 34411415, 34958143, 34459887, 30868567, 15928039) -

Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Mar 27, 2018

- -

Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 11, 2015

The p.Ala72Thr variant in PTPN11 has been identified by our laboratory as a de n ovo occurrence in one fetus with an increased NT measurement. It was absent from large population studies. This variant has also been reported as a somatic chan ge in at least 5 individuals with juvenile myelomonocytic leukemia (JMML; Kratz 2005, Tartaglia 2006). In addition, different amino acid changes at this positio n (p.Ala72Ser, p.Ala72Gly, p.Ala72Pro) have been reported in the germline of sev eral individuals with clinical features of Noonan syndrome (Kratz 2005, Tartagli a 2003, Lee 2008, LMM unpublished data). Computational prediction tools and cons ervation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, alt hough additional studies are required to fully establish its clinical significan ce, the p.Ala72Thr variant is likely pathogenic. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 29, 2019

Variant summary: PTPN11 c.214G>A (p.Ala72Thr) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Overlapping variants at Ala72 and adjacent codons have been implicated in Noonan syndrome (e.g., p.A72G, p.A72P, p.A72S), suggesting the codon and motif are critical for proper protein function. The variant was absent in 251056 control chromosomes. c.214G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions such as JMML, and prenatally diagnosed CHD/Noonan syndrome ((Kratz_2005, Mason-Suares_2017, Westphal_2019). One of these publications reported the identification of this variant as a confirmed de-novo variant following trio-based exome sequence analysis (Westphal_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.85
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	.;.;.;D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.1	L;L;.;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	D;D;.;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Uncertain	0.010	D;D;.;D
Polyphen		0.99	D;D;.;.
Vest4		0.85
MutPred		0.65		Loss of ubiquitination at K70 (P = 0.1264);Loss of ubiquitination at K70 (P = 0.1264);Loss of ubiquitination at K70 (P = 0.1264);Loss of ubiquitination at K70 (P = 0.1264);
MVP		0.95
MPC		1.9
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.66

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: rs121918453; hg19: chr12-112888198; COSMIC: COSV61004775; COSMIC: COSV61004775;