12-112419124-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_002834.5(PTPN11):c.13A>G(p.Arg5Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R5R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PTPN11
NM_002834.5 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.59

Publications

1 publications found

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]

PTPN11 Gene-Disease associations (from GenCC):

LEOPARD syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Noonan syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
metachondromatosis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PTPN11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 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, 9 uncertain in NM_002834.5

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 Costello syndrome, Noonan syndrome 1, Noonan syndrome, LEOPARD syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, metachondromatosis.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.13A>G	p.Arg5Gly	missense_variant, splice_region_variant	Exon 1 of 16	ENST00000351677.7	NP_002825.3	Q06124-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 link	c.13A>G	p.Arg5Gly	missense_variant, splice_region_variant	Exon 1 of 16	1	NM_002834.5	ENSP00000340944.3		Q06124-2
PTPN11	ENST00000635625.1 link	c.13A>G	p.Arg5Gly	missense_variant, splice_region_variant	Exon 1 of 15	5		ENSP00000489597.1		Q06124-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1371084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

676506

African (AFR)

AF:

0.00

AC:

AN:

28586

American (AMR)

AF:

0.00

AC:

AN:

34200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24446

East Asian (EAS)

AF:

0.00

AC:

AN:

33434

South Asian (SAS)

AF:

0.00

AC:

AN:

77086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4010

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070186

Other (OTH)

AF:

0.00

AC:

AN:

56926

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

CardioboostCm

Uncertain

0.89

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

.;.;.;D

Eigen

Benign

0.081

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.82

T;T;T;T

M_CAP

Pathogenic

0.99

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

1.5

L;L;.;L

PhyloP100

1.6

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.8

D;D;.;.

REVEL

Uncertain

0.56

Sift

Benign

0.10

T;T;.;.

Sift4G

Uncertain

0.0030

D;D;.;D

Polyphen

0.33

B;B;.;.

Vest4

0.25

MutPred

0.52

Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);

MVP

0.78

MPC

2.0

ClinPred

0.98

GERP RS

4.7

PromoterAI

0.055

Neutral

(source)

Varity_R

0.70

gMVP

0.75

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.25

Position offset: -44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over