NM_002834.5:c.558G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.558G>T (p.Arg186=) variant in the PTPN11 gene is 0.231% (49/16504) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA181422/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.00018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 2 hom. )

Consequence

PTPN11
NM_002834.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:17

Conservation

PhyloP100: 0.880

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

PTPN11 links:

ENSG00000305447 (HGNC:):

ENSG00000305447 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN11	NM_002834.5	MANE Select	c.558G>T	p.Arg186Arg	synonymous	Exon 5 of 16	NP_002825.3
PTPN11	NM_001330437.2		c.558G>T	p.Arg186Arg	synonymous	Exon 5 of 16	NP_001317366.1	Q06124-1
PTPN11	NM_001374625.1		c.555G>T	p.Arg185Arg	synonymous	Exon 5 of 16	NP_001361554.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.558G>T	p.Arg186Arg	synonymous	Exon 5 of 16	ENSP00000340944.3	Q06124-2
PTPN11	ENST00000635625.1	TSL:5	c.558G>T	p.Arg186Arg	synonymous	Exon 5 of 15	ENSP00000489597.1	Q06124-1
PTPN11	ENST00000392597.5	TSL:1	c.558G>T	p.Arg186Arg	synonymous	Exon 5 of 11	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000474

AC:

119

AN:

251082

AF XY:

0.000626

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000268

AC:

391

AN:

1461480

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

266

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33472

American (AMR)

AF:

0.000112

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00278

AC:

240

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00141

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.000103

AC:

114

AN:

1111768

Other (OTH)

AF:

0.000348

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000184

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68032

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000278

Hom.:

Bravo

AF:

0.000144

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Metachondromatosis (2)

not provided (2)

RASopathy (2)

Cardiovascular phenotype (1)

Juvenile myelomonocytic leukemia (1)

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)

LEOPARD syndrome 1 (1)

Noonan syndrome 1 (1)

Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

0.88

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over