12-112502049-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002834.5(PTPN11):c.1600-95C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 938,236 control chromosomes in the GnomAD database, including 47,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 15327 hom., cov: 32)

Exomes 𝑓: 0.23 ( 32404 hom. )

Consequence

PTPN11
NM_002834.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.93

Publications

15 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 12-112502049-C-T is Benign according to our data. Variant chr12-112502049-C-T is described in ClinVar as Benign. ClinVar VariationId is 40569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.83 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.1600-95C>T	intron_variant	Intron 13 of 15	ENST00000351677.7	NP_002825.3	Q06124-2
PTPN11	NM_001330437.2 link	c.1612-95C>T	intron_variant	Intron 13 of 15		NP_001317366.1	Q06124-1
PTPN11	NM_001374625.1 link	c.1597-95C>T	intron_variant	Intron 13 of 15		NP_001361554.1
PTPN11	XM_011538613.3 link	c.1609-95C>T	intron_variant	Intron 13 of 15		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 link	c.1600-95C>T		intron_variant	Intron 13 of 15	1	NM_002834.5	ENSP00000340944.3		Q06124-2
PTPN11	ENST00000635625.1 link	c.1612-95C>T		intron_variant	Intron 13 of 14	5		ENSP00000489597.1		Q06124-1

Frequencies

GnomAD3 genomes

AF:

0.368

AC:

55917

AN:

151820

Hom.:

15287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.724

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.340

Gnomad ASJ

AF:

0.0957

Gnomad EAS

AF:

0.851

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.178

Gnomad OTH

AF:

0.340

GnomAD4 exome

AF:

0.234

AC:

183797

AN:

786298

Hom.:

32404

AF XY:

0.231

AC XY:

95196

AN XY:

411626

show subpopulations

African (AFR)

AF:

0.725

AC:

13733

AN:

18948

American (AMR)

AF:

0.362

AC:

12154

AN:

33548

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

2237

AN:

21060

East Asian (EAS)

AF:

0.828

AC:

28127

AN:

33988

South Asian (SAS)

AF:

0.274

AC:

17987

AN:

65694

European-Finnish (FIN)

AF:

0.156

AC:

7746

AN:

49636

Middle Eastern (MID)

AF:

0.294

AC:

849

AN:

2890

European-Non Finnish (NFE)

AF:

0.174

AC:

91146

AN:

523052

Other (OTH)

AF:

0.262

AC:

9818

AN:

37482

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

6317

12634

18951

25268

31585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2262

4524

6786

9048

11310

<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:

0.369

AC:

56013

AN:

151938

Hom.:

15327

Cov.:

AF XY:

0.368

AC XY:

27312

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.725

AC:

30036

AN:

41454

American (AMR)

AF:

0.340

AC:

5191

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.0957

AC:

332

AN:

3468

East Asian (EAS)

AF:

0.851

AC:

4407

AN:

5180

South Asian (SAS)

AF:

0.297

AC:

1430

AN:

4808

European-Finnish (FIN)

AF:

0.153

AC:

1614

AN:

10546

Middle Eastern (MID)

AF:

0.353

AC:

103

AN:

292

European-Non Finnish (NFE)

AF:

0.178

AC:

12058

AN:

67918

Other (OTH)

AF:

0.336

AC:

709

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1317

2635

3952

5270

6587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.260

Hom.:

1620

Bravo

AF:

0.405

Asia WGS

AF:

0.525

AC:

1826

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.14

(source)

DANN

Benign

0.21

PhyloP100

-1.9

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over