chr12-112455968-A-T
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP2
The NM_002834.5(PTPN11):c.661A>T(p.Ile221Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I221V) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 31)
Consequence
PTPN11
NM_002834.5 missense
NM_002834.5 missense
Scores
8
5
6
Clinical Significance
Conservation
PhyloP100: 8.88
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 Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-112455970-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 981584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant where missense usually causes diseases, PTPN11
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTPN11 | NM_002834.5 | c.661A>T | p.Ile221Leu | missense_variant | 6/16 | ENST00000351677.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTPN11 | ENST00000351677.7 | c.661A>T | p.Ile221Leu | missense_variant | 6/16 | 1 | NM_002834.5 | A1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 12, 2012 | The Ile221Leu variant in the PTPN11 gene has not been reported in the literature nor previously identified by our laboratory. In addition, this variant has not been identified in large and broad populations by NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemical amino a cid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide str ong support for or against an impact to the protein. In summary, additional info rmation is needed to fully assess the clinical significance of the Ile221Leu var iant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;.
REVEL
Pathogenic
Sift
Benign
T;T;.
Sift4G
Benign
T;T;T
Polyphen
B;B;.
Vest4
MutPred
Gain of disorder (P = 0.0957);Gain of disorder (P = 0.0957);Gain of disorder (P = 0.0957);
MVP
MPC
0.84
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at