12-112477619-A-C

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.854-32A>C variant in the PTPN11 gene is 15.2% for Latino chromosomes by the Exome Aggregation Consortium (1824/11514 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA215447/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.0086 ( 71 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 492 hom. )

Consequence

PTPN11
NM_002834.5 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: -0.270

Publications

0 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: 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	Effect	Exon Rank	Protein
PTPN11	NM_002834.5	MANE Select	c.854-32A>C	intron	N/A	NP_002825.3
PTPN11	NM_001330437.2		c.854-32A>C	intron	N/A	NP_001317366.1
PTPN11	NM_001374625.1		c.851-32A>C	intron	N/A	NP_001361554.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.854-32A>C	intron	N/A	ENSP00000340944.3
PTPN11	ENST00000635625.1	TSL:5	c.854-32A>C	intron	N/A	ENSP00000489597.1
PTPN11	ENST00000392597.5	TSL:1	c.854-32A>C	intron	N/A	ENSP00000376376.1

Frequencies

GnomAD3 genomes

AF:

0.00857

AC:

1302

AN:

151866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0791

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.0154

GnomAD2 exomes

AF:

0.0204

AC:

5120

AN:

251128

AF XY:

0.0149

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.00446

AC:

6220

AN:

1395898

Hom.:

492

Cov.:

AF XY:

0.00359

AC XY:

2510

AN XY:

698430

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

32018

American (AMR)

AF:

0.134

AC:

5977

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25736

East Asian (EAS)

AF:

0.00

AC:

AN:

39390

South Asian (SAS)

AF:

0.00

AC:

AN:

84904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4150

European-Non Finnish (NFE)

AF:

0.0000237

AC:

AN:

1053574

Other (OTH)

AF:

0.00310

AC:

180

AN:

58106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

314

628

943

1257

1571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00861

AC:

1309

AN:

151984

Hom.:

Cov.:

AF XY:

0.00993

AC XY:

738

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.00150

AC:

AN:

41426

American (AMR)

AF:

0.0795

AC:

1211

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67976

Other (OTH)

AF:

0.0152

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.0118

Hom.:

Bravo

AF:

0.0165

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 12, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Jun 03, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Noonan syndrome

Benign:1

May 29, 2014

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

RASopathy

Benign:1

Apr 03, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The filtering allele frequency of the c.854-32A>C variant in the PTPN11 gene is 15.2% for Latino chromosomes by the Exome Aggregation Consortium (1824/11514 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.19

(source)

DANN

Benign

0.38

PhyloP100

-0.27

PromoterAI

0.088

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over