12-112455968-A-T

Position:

• chr12-112455968-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
CardioboostCm	Uncertain	0.27
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Benign	0.035
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.5	N;N;.
REVEL	Pathogenic	0.69
Sift	Benign	0.088	T;T;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.52
MutPred		0.32		Gain of disorder (P = 0.0957);Gain of disorder (P = 0.0957);Gain of disorder (P = 0.0957);
MVP		0.98
MPC		0.84
ClinPred		0.92	D
GERP RS		5.0
Varity_R		0.69
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs397516806; hg19: chr12-112893772;