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rs121918461

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_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

Scores

12
6
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.31
Variant links:
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]

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ACMG classification

Classification made for transcript

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 where missense usually causes diseases, PTPN11
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
PTPN11NM_002834.5 linkuse as main transcriptc.182A>C p.Asp61Ala missense_variant 3/16 ENST00000351677.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTPN11ENST00000351677.7 linkuse as main transcriptc.182A>C p.Asp61Ala missense_variant 3/161 NM_002834.5 A1Q06124-2

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
LINK: link

Submissions by phenotype

Noonan syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 09, 2013The 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 20, 2018Variant 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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