chr12-112504777-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002834.5(PTPN11):c.*13A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000447 in 1,549,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.522

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: 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 12-112504777-A-G is Benign according to our data. Variant chr12-112504777-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.*13A>G	3_prime_UTR_variant	Exon 15 of 16	ENST00000351677.7	NP_002825.3	Q06124-2
PTPN11	NM_001330437.2 link	c.*13A>G	3_prime_UTR_variant	Exon 15 of 16		NP_001317366.1	Q06124-1
PTPN11	NM_001374625.1 link	c.*13A>G	3_prime_UTR_variant	Exon 15 of 16		NP_001361554.1
PTPN11	XM_011538613.3 link	c.*13A>G	3_prime_UTR_variant	Exon 15 of 16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 link	c.*13A>G		3_prime_UTR_variant	Exon 15 of 16	1	NM_002834.5	ENSP00000340944.3		Q06124-2
PTPN11	ENST00000635625.1 link	c.*13A>G		downstream_gene_variant		5		ENSP00000489597.1		Q06124-1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000332

AC:

AN:

250256

AF XY:

0.000318

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.000593

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000468

AC:

653

AN:

1396734

Hom.:

Cov.:

AF XY:

0.000482

AC XY:

336

AN XY:

697766

show subpopulations

African (AFR)

AF:

0.0000940

AC:

AN:

31928

American (AMR)

AF:

0.0000448

AC:

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25780

East Asian (EAS)

AF:

0.00

AC:

AN:

39340

South Asian (SAS)

AF:

0.00

AC:

AN:

84800

European-Finnish (FIN)

AF:

0.000300

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.000573

AC:

603

AN:

1052992

Other (OTH)

AF:

0.000498

AC:

AN:

58280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000256

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41584

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

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:

0.000371

Hom.:

Bravo

AF:

0.000249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 07, 2013

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. -

Oct 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.*13A>G in the 3'UTR of PTPN11: This variant is not expected to have clinical significance because it has been identified in 0.1% (43/62072) of European chrom osomes by the Exome Aggregation Constortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs201957261). -

Apr 05, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.47

(source)

DANN

Benign

0.83

PhyloP100

-0.52

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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