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GeneBe

rs121918457

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_002834.5(PTPN11):c.1403C>A(p.Thr468Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T468M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PTPN11
NM_002834.5 missense

Scores

15
2
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57
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 11 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr12-112488466-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13331.Status of the report is reviewed_by_expert_panel, 3 stars.
PP2
Missense variant where missense usually causes diseases, PTPN11
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTPN11NM_002834.5 linkuse as main transcriptc.1403C>A p.Thr468Lys missense_variant 12/16 ENST00000351677.7
PTPN11NM_001330437.2 linkuse as main transcriptc.1415C>A p.Thr472Lys missense_variant 12/16
PTPN11NM_001374625.1 linkuse as main transcriptc.1400C>A p.Thr467Lys missense_variant 12/16
PTPN11XM_011538613.3 linkuse as main transcriptc.1412C>A p.Thr471Lys missense_variant 12/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTPN11ENST00000351677.7 linkuse as main transcriptc.1403C>A p.Thr468Lys missense_variant 12/161 NM_002834.5 A1Q06124-2

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
1.0
CardioboostCm
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
31
Dann
Uncertain
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.92
D
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-5.6
D;.;.
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;.;.
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.91
MutPred
0.88
Gain of methylation at T468 (P = 0.0119);.;.;
MVP
0.99
MPC
2.1
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: chr12-112926270; API