chr12-112477630-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.854-21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0705 in 1,584,378 control chromosomes in the GnomAD database, including 4,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 315 hom., cov: 32)

Exomes 𝑓: 0.072 ( 4080 hom. )

Consequence

PTPN11
NM_002834.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.278

Publications

10 publications found

Variant links:

COSMIC-nc: COSV61012275

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=-0.9).

BP6

Variant 12-112477630-C-T is Benign according to our data. Variant chr12-112477630-C-T is described in ClinVar as Benign. ClinVar VariationId is 40532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0775 is higher than 0.05.

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.854-21C>T	intron	N/A	NP_002825.3
PTPN11	NM_001330437.2		c.854-21C>T	intron	N/A	NP_001317366.1
PTPN11	NM_001374625.1		c.851-21C>T	intron	N/A	NP_001361554.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.854-21C>T	intron	N/A	ENSP00000340944.3
PTPN11	ENST00000635625.1	TSL:5	c.854-21C>T	intron	N/A	ENSP00000489597.1
PTPN11	ENST00000392597.5	TSL:1	c.854-21C>T	intron	N/A	ENSP00000376376.1

Frequencies

GnomAD3 genomes

AF:

0.0564

AC:

8569

AN:

151944

Hom.:

315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0238

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.0665

Gnomad ASJ

AF:

0.0553

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0460

Gnomad FIN

AF:

0.0404

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.0793

Gnomad OTH

AF:

0.0844

GnomAD2 exomes

AF:

0.0581

AC:

14589

AN:

251218

AF XY:

0.0597

show subpopulations

Gnomad AFR exome

AF:

0.0212

Gnomad AMR exome

AF:

0.0482

Gnomad ASJ exome

AF:

0.0589

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0339

Gnomad NFE exome

AF:

0.0820

Gnomad OTH exome

AF:

0.0692

GnomAD4 exome

AF:

0.0720

AC:

103117

AN:

1432314

Hom.:

4080

Cov.:

AF XY:

0.0712

AC XY:

50830

AN XY:

714394

show subpopulations

African (AFR)

AF:

0.0220

AC:

721

AN:

32812

American (AMR)

AF:

0.0497

AC:

2221

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0600

AC:

1559

AN:

25984

East Asian (EAS)

AF:

0.000253

AC:

AN:

39584

South Asian (SAS)

AF:

0.0482

AC:

4120

AN:

85562

European-Finnish (FIN)

AF:

0.0356

AC:

1903

AN:

53410

Middle Eastern (MID)

AF:

0.114

AC:

494

AN:

4316

European-Non Finnish (NFE)

AF:

0.0810

AC:

88024

AN:

1086588

Other (OTH)

AF:

0.0685

AC:

4065

AN:

59376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

4856

9711

14567

19422

24278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3102

6204

9306

12408

15510

<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:

0.0563

AC:

8562

AN:

152064

Hom.:

315

Cov.:

AF XY:

0.0545

AC XY:

4048

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0237

AC:

984

AN:

41488

American (AMR)

AF:

0.0664

AC:

1013

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.0553

AC:

192

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5182

South Asian (SAS)

AF:

0.0461

AC:

222

AN:

4820

European-Finnish (FIN)

AF:

0.0404

AC:

426

AN:

10550

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0793

AC:

5389

AN:

67988

Other (OTH)

AF:

0.0825

AC:

174

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

422

844

1265

1687

2109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0678

Hom.:

279

Bravo

AF:

0.0573

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 28, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PTPN11 c.854-21C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SRp40, SF2/ASF and SC35. However, these predictions have yet to be confirmed by functional studies. This variant was found in 15911/276874 control chromosomes (626 homozygotes) at a frequency of 0.0574666, which is approximately 900 times the estimated maximal expected allele frequency of a pathogenic PTPN11 variant (0.0000625), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.

Mar 01, 2013

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

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

Metachondromatosis

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Juvenile myelomonocytic leukemia

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Noonan syndrome

Benign:1

Sep 25, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.1

(source)

DANN

Benign

0.64

PhyloP100

-0.28

PromoterAI

-0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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