rs121918461

Positions:

• chr12-112450362-A-C
• chr12-112450362-A-G
• chr12-112450362-A-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.182A>C​(p.Asp61Ala) 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. D61Y) 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: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 19 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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 chr12-112450362-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13330.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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 12-112450362-A-C is Pathogenic according to our data. Variant chr12-112450362-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.182A>C	p.Asp61Ala	missense_variant	3/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.182A>C	p.Asp61Ala	missense_variant	3/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 09, 2013

The Asp61Ala variant has not been previously identified by our laboratory, nor h as it been identified in large population studies. This variant has been reporte d in the literature in one fetus with a diagnosis of Noonan syndrome and fetal c hylothorax (Chen 2009). In addition, two other variants at this position have be en identified in >25 individuals with clinical features of Noonan syndrome by ou r laboratory and in the literature (Asp61Asn and Asp61Gly; Loh 2004, Tartaglia 2 005, Tartaglia 2006, Kratz 2005, Yamamoto 2006, Kosaki 2002, Bertola 2006, Noord am 2008, Shaw 2007, Tartaglia 2001). The Asp residue at this position is highly conserved across evolutionarily distinct species, and computational analyses (bi ochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that th e Asp61Ala variant may have impact to the protein. In summary, this variant is l ikely pathogenic, though additional studies are required to fully establish its clinical significance. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 20, 2018

Variant summary: PTPN11 c.182A>C (p.Asp61Ala) 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. The variant was absent in 245776 control chromosomes (gnomAD). The variant, c.182A>C, has been reported in the literature in a fetus affected with Noonan Syndrome and Related Conditions (Chen 2009). In addition, other variants affecting this position, Asp61Asn and Asp61Gly, has been reported in several affected individuals. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating an increased basal activity of protein tyrosine phosphatase (OReilly 2000). 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 pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.83
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.5	D;D;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0030	D;D;.;.
Sift4G	Uncertain	0.0050	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.94
MutPred		0.92		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.81

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: rs121918461; hg19: chr12-112888166; COSMIC: COSV61011211; COSMIC: COSV61011211;