rs1555267561

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_002834.5(PTPN11):​c.223G>A​(p.Ala75Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

PTPN11
NM_002834.5 missense

Scores

4
8
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.99
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 Uncertain_significance. Variant got 5 ACMG points.

PM1
In a domain SH2 1 (size 96) in uniprot entity PTN11_HUMAN there are 61 pathogenic changes around while only 0 benign (100%) in NM_002834.5
PM2
Very rare variant in population databases, with high coverage;
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). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. GenCC has associacion of the 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTPN11NM_002834.5 linkc.223G>A p.Ala75Thr missense_variant 3/16 ENST00000351677.7 NP_002825.3 Q06124-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTPN11ENST00000351677.7 linkc.223G>A p.Ala75Thr missense_variant 3/161 NM_002834.5 ENSP00000340944.3 Q06124-2
PTPN11ENST00000635625.1 linkc.223G>A p.Ala75Thr missense_variant 3/155 ENSP00000489597.1 Q06124-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
CardioboostCm
Uncertain
0.11
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Uncertain
23
DANN
Benign
0.97
DEOGEN2
Uncertain
0.44
.;.;.;T
Eigen
Benign
0.025
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.78
T;T;T;T
M_CAP
Uncertain
0.10
D
MetaRNN
Uncertain
0.49
T;T;T;T
MetaSVM
Uncertain
-0.28
T
MutationAssessor
Benign
0.060
N;N;.;N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.4
N;N;.;.
REVEL
Uncertain
0.39
Sift
Benign
0.49
T;T;.;.
Sift4G
Benign
0.56
T;T;.;T
Polyphen
0.065
B;B;.;.
Vest4
0.80
MutPred
0.50
Loss of ubiquitination at K70 (P = 0.1264);Loss of ubiquitination at K70 (P = 0.1264);Loss of ubiquitination at K70 (P = 0.1264);Loss of ubiquitination at K70 (P = 0.1264);
MVP
0.91
MPC
1.9
ClinPred
0.72
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.82
gMVP
0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-112888207; API