rs143433437

chr12-112454594-C-Gchr12-112454594-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002834.5(PTPN11):c.556C>G(p.Arg186Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R186W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.55

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.556C>G	p.Arg186Gly	missense_variant	5/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.556C>G	p.Arg186Gly	missense_variant	5/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
CardioboostCm	Benign	0.038
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	0.021
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Benign	1.2	L;L;.;L
MutationTaster	Benign	0.93	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D;D;.;.
REVEL	Uncertain	0.49
Sift	Benign	0.28	T;T;.;.
Sift4G	Benign	0.14	T;T;.;T
Polyphen		0.0010	B;B;.;.
Vest4		0.45
MutPred		0.70		Loss of catalytic residue at R186 (P = 0.0639);Loss of catalytic residue at R186 (P = 0.0639);Loss of catalytic residue at R186 (P = 0.0639);Loss of catalytic residue at R186 (P = 0.0639);
MVP		0.93
MPC		1.3
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.82
gMVP		0.57

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: chr12-112892398;