rs1060502526

Variant names:

• chr12-112502219-C-T
• rs1060502526
• NM_002834.5:c.1675C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002834.5(PTPN11):​c.1675C>T​(p.Pro559Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.18

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PTPN11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.1293 (above the threshold of 3.09). Trascript score misZ: 4.9438 (above the threshold of 3.09). GenCC associations: The gene is linked to Noonan syndrome and Noonan-related syndrome, Noonan syndrome with multiple lentigines, metachondromatosis, Noonan syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome 1, Costello syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27548307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1675C>T	p.Pro559Ser	missense_variant	Exon 14 of 16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1687C>T	p.Pro563Ser	missense_variant	Exon 14 of 16		NP_001317366.1
PTPN11	NM_001374625.1	c.1672C>T	p.Pro558Ser	missense_variant	Exon 14 of 16		NP_001361554.1
PTPN11	XM_011538613.3	c.1684C>T	p.Pro562Ser	missense_variant	Exon 14 of 16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1675C>T	p.Pro559Ser	missense_variant	Exon 14 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1687C>T	p.Pro563Ser	missense_variant	Exon 14 of 15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

RASopathy Uncertain:1

Apr 24, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with serine at codon 559 of the PTPN11 protein (p.Pro559Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PTPN11-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
CardioboostCm	Benign	0.0043
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T
Eigen	Benign	-0.058
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.090	N;.
REVEL	Benign	0.21
Sift	Benign	0.14	T;.
Sift4G	Benign	0.13	T;T
Polyphen		0.023	B;.
Vest4		0.63
MutPred		0.13		Gain of glycosylation at P559 (P = 0.0294);.;
MVP		0.39
MPC		1.4
ClinPred		0.89	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs1060502526; hg19: chr12-112940023;