12-112486902-G-A

Variant names:

Variant summary

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

The ENST00000392597.5(PTPN11):c.*269G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 1,393,526 control chromosomes in the GnomAD database, including 1,945 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 180 hom., cov: 32)

Exomes 𝑓: 0.049 ( 1765 hom. )

Consequence

PTPN11
ENST00000392597.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0380

Publications

4 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=-0.87).

BP6

Variant 12-112486902-G-A is Benign according to our data. Variant chr12-112486902-G-A is described in ClinVar as Benign. ClinVar VariationId is 561856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.072 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.1379+273G>A		intron_variant	Intron 11 of 15	ENST00000351677.7	NP_002825.3	Q06124-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PTPN11	ENST00000351677.7 link	c.1379+273G>A	intron_variant	Intron 11 of 15	1	NM_002834.5	ENSP00000340944.3	Q06124-2
PTPN11	ENST00000635625.1 link	c.1391+273G>A	intron_variant	Intron 11 of 14	5		ENSP00000489597.1	Q06124-1
PTPN11	ENST00000635652.1 link	c.392+273G>A	intron_variant	Intron 3 of 4	3		ENSP00000489541.1	A0A0U1RRI0

Frequencies

GnomAD3 genomes

AF:

0.0393

AC:

5986

AN:

152150

Hom.:

180

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00714

Gnomad AMI

AF:

0.154

Gnomad AMR

AF:

0.0306

Gnomad ASJ

AF:

0.0285

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0791

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0506

Gnomad OTH

AF:

0.0330

GnomAD4 exome

AF:

0.0490

AC:

60810

AN:

1241258

Hom.:

1765

Cov.:

AF XY:

0.0498

AC XY:

29816

AN XY:

598224

show subpopulations

African (AFR)

AF:

0.00624

AC:

172

AN:

27584

American (AMR)

AF:

0.0233

AC:

425

AN:

18228

Ashkenazi Jewish (ASJ)

AF:

0.0324

AC:

584

AN:

18018

East Asian (EAS)

AF:

0.000252

AC:

AN:

31798

South Asian (SAS)

AF:

0.0778

AC:

4587

AN:

58982

European-Finnish (FIN)

AF:

0.0938

AC:

2529

AN:

26972

Middle Eastern (MID)

AF:

0.0393

AC:

133

AN:

3382

European-Non Finnish (NFE)

AF:

0.0498

AC:

50023

AN:

1005238

Other (OTH)

AF:

0.0460

AC:

2349

AN:

51056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2508

5017

7525

10034

12542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2040

4080

6120

8160

10200

<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:

0.0393

AC:

5982

AN:

152268

Hom.:

180

Cov.:

AF XY:

0.0422

AC XY:

3139

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00712

AC:

296

AN:

41564

American (AMR)

AF:

0.0306

AC:

468

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0285

AC:

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.0785

AC:

379

AN:

4828

European-Finnish (FIN)

AF:

0.101

AC:

1069

AN:

10600

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0507

AC:

3445

AN:

68012

Other (OTH)

AF:

0.0326

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

286

572

859

1145

1431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0439

Hom.:

226

Bravo

AF:

0.0309

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Jun 19, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.5

(source)

DANN

Benign

0.67

PhyloP100

0.038

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