Genetic Variant NM_001109754.4:c.1033A>G (chr12-70596274-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001109754.4(PTPRB):c.1033A>G(p.Ser345Gly) variant causes a missense change. The variant allele was found at a frequency of 0.283 in 1,610,220 control chromosomes in the GnomAD database, including 66,100 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7493 hom., cov: 28)

Exomes 𝑓: 0.28 ( 58607 hom. )

Consequence

PTPRB
NM_001109754.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.00

Publications

31 publications found

Variant links:

Genes affected

PTPRB (HGNC:9665): (protein tyrosine phosphatase receptor type B) 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 an extracellular domain, a single transmembrane segment and one intracytoplasmic catalytic domain, thus belongs to receptor type PTP. The extracellular region of this PTP is composed of multiple fibronectin type_III repeats, which was shown to interact with neuronal receptor and cell adhesion molecules, such as contactin and tenascin C. This protein was also found to interact with sodium channels, and thus may regulate sodium channels by altering tyrosine phosphorylation status. The functions of the interaction partners of this protein implicate the roles of this PTP in cell adhesion, neurite growth, and neuronal differentiation. Alternate transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

PTPRB links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005496502).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPRB	NM_001109754.4 link	c.1033A>G	p.Ser345Gly	missense_variant	Exon 5 of 34	ENST00000334414.11	NP_001103224.1	P23467-3Q86VA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPRB	ENST00000334414.11 link	c.1033A>G	p.Ser345Gly	missense_variant	Exon 5 of 34	1	NM_001109754.4	ENSP00000334928.6		P23467-3

Frequencies

GnomAD3 genomes

AF:

0.308

AC:

46315

AN:

150446

Hom.:

7479

Cov.:

show subpopulations

Gnomad AFR

AF:

0.416

Gnomad AMI

AF:

0.143

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.314

Gnomad SAS

AF:

0.283

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.313

GnomAD2 exomes

AF:

0.267

AC:

65929

AN:

246676

AF XY:

0.268

show subpopulations

Gnomad AFR exome

AF:

0.422

Gnomad AMR exome

AF:

0.190

Gnomad ASJ exome

AF:

0.244

Gnomad EAS exome

AF:

0.296

Gnomad FIN exome

AF:

0.238

Gnomad NFE exome

AF:

0.274

Gnomad OTH exome

AF:

0.270

GnomAD4 exome

AF:

0.281

AC:

410063

AN:

1459662

Hom.:

58607

Cov.:

AF XY:

0.280

AC XY:

203250

AN XY:

725934

show subpopulations

African (AFR)

AF:

0.420

AC:

14058

AN:

33440

American (AMR)

AF:

0.199

AC:

8853

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

6234

AN:

26098

East Asian (EAS)

AF:

0.309

AC:

12276

AN:

39670

South Asian (SAS)

AF:

0.267

AC:

22936

AN:

85988

European-Finnish (FIN)

AF:

0.236

AC:

12531

AN:

53100

Middle Eastern (MID)

AF:

0.246

AC:

1418

AN:

5756

European-Non Finnish (NFE)

AF:

0.283

AC:

314751

AN:

1110782

Other (OTH)

AF:

0.282

AC:

17006

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

16408

32816

49225

65633

82041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10648

21296

31944

42592

53240

<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:

0.308

AC:

46365

AN:

150558

Hom.:

7493

Cov.:

AF XY:

0.305

AC XY:

22366

AN XY:

73416

show subpopulations

African (AFR)

AF:

0.416

AC:

17008

AN:

40874

American (AMR)

AF:

0.242

AC:

3649

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

846

AN:

3462

East Asian (EAS)

AF:

0.314

AC:

1603

AN:

5106

South Asian (SAS)

AF:

0.283

AC:

1352

AN:

4774

European-Finnish (FIN)

AF:

0.232

AC:

2373

AN:

10230

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.276

AC:

18678

AN:

67776

Other (OTH)

AF:

0.313

AC:

654

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1513

3025

4538

6050

7563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.286

Hom.:

21105

Bravo

AF:

0.313

TwinsUK

AF:

0.285

AC:

1055

ALSPAC

AF:

0.287

AC:

1108

ESP6500AA

AF:

0.397

AC:

1481

ESP6500EA

AF:

0.278

AC:

2290

ExAC

AF:

0.272

AC:

32791

Asia WGS

AF:

0.279

AC:

974

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;T;.;.;T;T;T

Eigen

Benign

-0.037

Eigen_PC

Benign

0.056

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.70

T;T;T;T;T;T;T

MetaRNN

Benign

0.0055

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

.;.;M;M;M;.;.

PhyloP100

4.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

N;N;N;N;N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.014

D;D;D;T;T;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D

Polyphen

0.0070

B;B;.;B;B;B;B

Vest4

0.66

MPC

0.10

ClinPred

0.039

GERP RS

5.8

Varity_R

0.25

gMVP

0.59

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Computational scores

Splicing

Publications

Other links and lift over