rs121918465

Positions:

• chr12-112450407-A-C
• chr12-112450407-A-G
• chr12-112450407-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_002834.5(PTPN11):​c.227A>C​(p.Glu76Ala) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E76D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.31

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 11 ACMG points.

• PM1: In a helix (size 8) in uniprot entity PTN11_HUMAN there are 16 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 chr12-112450408-G-C 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, 0.933
• PP5: Variant 12-112450407-A-C is Pathogenic according to our data. Variant chr12-112450407-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 13339.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-112450407-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.227A>C	p.Glu76Ala	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.227A>C	p.Glu76Ala	missense_variant	3/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.227A>C	p.Glu76Ala	missense_variant	3/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 27, 2016

The E76A variant has been reported previously as a somatic variation in patients diagnosed with Juvenile Myelomonocytic Leukemia (JMML) without Noonan syndrome (Shimada et al., 2004; Tartaglia et al., 2003). Missense variants in PTPN11 are found in approximately 34% of individuals with JMML without Noonan syndrome. The Glutamic acid 76 residue is an apparent hotspot, with multiple published missense variants (E76K/V/G) associated with JMML (Tartaglia et al., 2003). The E76A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies show that E76A, like other cancer associated variants in PTPN11, confers a greater gain-of-function than variants that are exclusively associated with Noonan syndrome (Kratz et al., 2005; O'Reilly et al., 2000). It is further presumed that the E76A variant is a somatic variant as cancer-associated variants confer a greater gain-of-function than variants exclusively associated with RASopathies and as a consequence are associated with severe prenatal abnormalities and demise. In a paper discussing sequence analysis of the PTPN11 gene in fetuses with ultrasound findings, two fetuses were found to have variants that were predominantly (F71L) or exclusively (T507K) reported in the context of cancer (Lee et al., 2008). Both of these fetuses presented with hydrops fetalis and one of these cases resulted in fetal demise (Lee et al., 2009). The presence of E76A is consistent with the diagnosis of JMML. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;.;.;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L;L;.;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.2	D;D;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Uncertain	0.010	D;D;.;D
Polyphen		0.99	D;D;.;.
Vest4		0.95
MutPred		0.79		Loss of phosphorylation at Y80 (P = 0.2041);Loss of phosphorylation at Y80 (P = 0.2041);Loss of phosphorylation at Y80 (P = 0.2041);Loss of phosphorylation at Y80 (P = 0.2041);
MVP		1.0
MPC		2.0
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Varity_R		0.97
gMVP		0.82

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: rs121918465; hg19: chr12-112888211; COSMIC: COSV61006382; COSMIC: COSV61006382;