chr12-112477651-T-A

Position:

• chr12-112477651-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_002834.5(PTPN11):​c.854T>A​(p.Phe285Tyr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. F285L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense, splice_region
• Scores: Splicing: ADA: 0.4260
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 5.89

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 16 ACMG points.

• PM1: In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 52 pathogenic changes around while only 2 benign (96%) 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 chr12-112473040-T-C is described in Lovd as [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, 0.77
• PP5: Variant 12-112477651-T-A is Pathogenic according to our data. Variant chr12-112477651-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.854T>A	p.Phe285Tyr	missense_variant, splice_region_variant	8/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.854T>A	p.Phe285Tyr	missense_variant, splice_region_variant	8/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.854T>A	p.Phe285Tyr	missense_variant, splice_region_variant	8/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2023

Not observed at significant frequency in large population cohorts (gnomAD); 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: 31573083, 33009502, 29493581, 30896080) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2018

The p.F285Y pathogenic mutation (also known as c.854T>A) is located in coding exon 8 of the PTPN11 gene. This change occurs in the first base pair of coding exon 8. The phenylalanine at codon 285 is replaced by tyrosine, an amino acid with highly similar properties. This mutation is located in the protein tyrosine phosphatase (PTP) functional domain of the SHP-2 protein, and is predicted to disrupt the interdomain interaction with the N-SH2 domain, which normally stabilizes the inactive conformation of the protein. Alterations at the same amino acid position (p.F285I, p.F285L, p.F285S and p.F285C) have been described in individuals with Noonan Syndrome (Tartaglia M et al, Am. J. Hum. Genet. 2002 Jun; 70(6):1555-63; Kosaki K et al, J. Clin. Endocrinol. Metab. 2002 Aug; 87(8):3529-33; Bertola DR et al, Genet. Test. 2006; 10(3):186-91; Tartaglia M et al, Am. J. Hum. Genet. 2006 Feb; 78(2):279-90; Ferrero GB et al, Eur J Med Genet 2008 Jul; 51(6):566-72; Essawi ML et al, J. Formos. Med. Assoc. 2013 Nov; 112(11):707-12). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

RASopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jun 07, 2021

Variant summary: PTPN11 c.854T>A (p.Phe285Tyr) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251350 control chromosomes (gnomAD). c.854T>A has been reported in the literature in individuals affected with Noonan syndrome or Noonan syndrome with multiple lentigines (Yu_2019). These data indicate that the variant may be associated with disease. Additionally, other variants at the same amino acid residue (Phe285Cys, Phe285Ile, Phe285Leu, Phe285Ser) have also been reported in association with Noonan syndrome, further supporting that this residue has clinical significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Noonan syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
CardioboostCm	Uncertain	0.58
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	.;.;D
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	-0.40	N;N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	D;N;.
REVEL	Pathogenic	0.79
Sift	Benign	0.44	T;T;.
Sift4G	Benign	0.77	T;T;T
Polyphen		0.44	B;B;.
Vest4		0.73
MutPred		0.76		Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);
MVP		0.89
MPC		0.94
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.43
dbscSNV1_RF	Pathogenic	0.74
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: rs121918463; hg19: chr12-112915455;