NM_002835.4:c.964G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_002835.4(PTPN12):c.964G>A(p.Val322Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,597,548 control chromosomes in the GnomAD database, including 315,015 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.69 ( 36948 hom., cov: 31)

Exomes 𝑓: 0.61 ( 278067 hom. )

Consequence

PTPN12
NM_002835.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.40

Publications

44 publications found

Variant links:

Genes affected

PTPN12 (HGNC:9645): (protein tyrosine phosphatase non-receptor type 12) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains a C-terminal PEST motif, which serves as a protein-protein interaction domain, and may regulate protein intracellular half-life. This PTP was found to bind and dephosphorylate the product of the oncogene c-ABL and thus may play a role in oncogenesis. This PTP was also shown to interact with, and dephosphorylate, various products related to cytoskeletal structure and cell adhesion, such as p130 (Cas), CAKbeta/PTK2B, PSTPIP1, and paxillin. This suggests it has a regulatory role in controlling cell shape and mobility. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

PTPN12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.785749E-7).

BP6

Variant 7-77618504-G-A is Benign according to our data. Variant chr7-77618504-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060850.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN12	NM_002835.4 link	c.964G>A	p.Val322Ile	missense_variant	Exon 12 of 18	ENST00000248594.11	NP_002826.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PTPN12	ENST00000248594.11 link	c.964G>A	p.Val322Ile	missense_variant	Exon 12 of 18	1	NM_002835.4	ENSP00000248594.6
PTPN12	ENST00000415482.6 link	c.607G>A	p.Val203Ile	missense_variant	Exon 12 of 18	5		ENSP00000392429.2
PTPN12	ENST00000435495.6 link	c.574G>A	p.Val192Ile	missense_variant	Exon 11 of 17	2		ENSP00000397991.2

Frequencies

GnomAD3 genomes

AF:

0.687

AC:

104266

AN:

151808

Hom.:

36898

Cov.:

show subpopulations

Gnomad AFR

AF:

0.830

Gnomad AMI

AF:

0.701

Gnomad AMR

AF:

0.755

Gnomad ASJ

AF:

0.686

Gnomad EAS

AF:

0.902

Gnomad SAS

AF:

0.701

Gnomad FIN

AF:

0.550

Gnomad MID

AF:

0.661

Gnomad NFE

AF:

0.588

Gnomad OTH

AF:

0.693

GnomAD2 exomes

AF:

0.673

AC:

166984

AN:

248078

AF XY:

0.663

show subpopulations

Gnomad AFR exome

AF:

0.831

Gnomad AMR exome

AF:

0.815

Gnomad ASJ exome

AF:

0.678

Gnomad EAS exome

AF:

0.899

Gnomad FIN exome

AF:

0.563

Gnomad NFE exome

AF:

0.590

Gnomad OTH exome

AF:

0.652

GnomAD4 exome

AF:

0.614

AC:

888205

AN:

1445622

Hom.:

278067

Cov.:

AF XY:

0.615

AC XY:

442508

AN XY:

719362

show subpopulations

African (AFR)

AF:

0.834

AC:

27588

AN:

33060

American (AMR)

AF:

0.804

AC:

35427

AN:

44060

Ashkenazi Jewish (ASJ)

AF:

0.679

AC:

17587

AN:

25888

East Asian (EAS)

AF:

0.920

AC:

36211

AN:

39372

South Asian (SAS)

AF:

0.677

AC:

57257

AN:

84516

European-Finnish (FIN)

AF:

0.564

AC:

29860

AN:

52954

Middle Eastern (MID)

AF:

0.662

AC:

3792

AN:

5728

European-Non Finnish (NFE)

AF:

0.583

AC:

641986

AN:

1100354

Other (OTH)

AF:

0.645

AC:

38497

AN:

59690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

14673

29346

44019

58692

73365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17794

35588

53382

71176

88970

<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:

0.687

AC:

104374

AN:

151926

Hom.:

36948

Cov.:

AF XY:

0.687

AC XY:

51049

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.830

AC:

34421

AN:

41462

American (AMR)

AF:

0.755

AC:

11529

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.686

AC:

2376

AN:

3466

East Asian (EAS)

AF:

0.902

AC:

4674

AN:

5180

South Asian (SAS)

AF:

0.700

AC:

3371

AN:

4814

European-Finnish (FIN)

AF:

0.550

AC:

5788

AN:

10516

Middle Eastern (MID)

AF:

0.684

AC:

201

AN:

294

European-Non Finnish (NFE)

AF:

0.588

AC:

39919

AN:

67912

Other (OTH)

AF:

0.693

AC:

1461

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1571

3141

4712

6282

7853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

808

1616

2424

3232

4040

<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:

0.627

Hom.:

75068

Bravo

AF:

0.706

TwinsUK

AF:

0.590

AC:

2187

ALSPAC

AF:

0.581

AC:

2238

ESP6500AA

AF:

0.827

AC:

3643

ESP6500EA

AF:

0.587

AC:

5049

ExAC

AF:

0.672

AC:

81569

Asia WGS

AF:

0.820

AC:

2851

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PTPN12-related disorder

Benign:1

Oct 16, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.069

T;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.80

T;T;T

MetaRNN

Benign

6.8e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.83

L;.;.

PhyloP100

2.4

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.32

N;N;N

REVEL

Benign

0.052

Sift

Benign

0.32

T;T;T

Sift4G

Benign

0.49

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.028

MPC

0.022

ClinPred

0.0057

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.034

gMVP

0.22

Mutation Taster

=92/8

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