rs397507518

chr12-112450508-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_002834.5(PTPN11):c.328G>A(p.Glu110Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E110G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 9.59

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112450509-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PTPN11
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• PP5: Variant 12-112450508-G-A is Pathogenic according to our data. Variant chr12-112450508-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450508-G-A is described in Lovd as [Pathogenic]. Variant chr12-112450508-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.328G>A	p.Glu110Lys	missense_variant	3/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.328G>A	p.Glu110Lys	missense_variant	3/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461534 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727094

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 21, 2014	The p.Glu110Lys variant in PTPN11 has been previously identified in three indivi duals with clinical features of Noonan syndrome (Ezquieta 2012, Rodriguez 2014, LMM unpublished data) and was reported to have occurred de novo in two of these individuals (Ezquieta 2012, LMM unpublished data). It was absent from large popu lation studies (http://evs.gs.washington.edu/EVS/; dbSNP rs397507518). In summar y, the p.Glu110Lys variant in PTPN11 meets our criteria to be classified as path ogenic (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medici ne/). -
Uncertain significance, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2023

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: 22465605, 29907801, 24451042, 30050098, 35769956, 24150203, 29493581, 35979676) -

Noonan syndrome 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 14, 2016

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 07, 2020

- -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 18, 2018

This sequence change replaces glutamic acid with lysine at codon 110 of the PTPN11 protein (p.Glu110Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in individuals affected with Noonan syndrome in the literature, including at least one individual where the variant was reported de novo (PMID: 22465605, 24150203, 24451042). ClinVar contains an entry for this variant (Variation ID: 40507). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.2	M;M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.6	D;D;.;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D;D;.;.
Sift4G	Uncertain	0.014	D;D;.;D
Polyphen		0.90	P;D;.;.
Vest4		0.95
MutPred		0.67		Gain of methylation at E110 (P = 0.01);Gain of methylation at E110 (P = 0.01);Gain of methylation at E110 (P = 0.01);Gain of methylation at E110 (P = 0.01);
MVP		0.97
MPC		2.0
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.96
gMVP		0.87

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: rs397507518; hg19: chr12-112888312;