chr4-86701350-T-G

Position:

chr4-86701350-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_080683.3(PTPN13):c.744T>G(p.Asp248Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000908 in 1,612,720 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 1 hom. )

Consequence

PTPN13
NM_080683.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0360

Variant links:

Genes affected

PTPN13 (HGNC:9646): (protein tyrosine phosphatase non-receptor type 13) 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 is a large intracellular protein. It has a catalytic PTP domain at its C-terminus and two major structural domains: a region with five PDZ domains and a FERM domain that binds to plasma membrane and cytoskeletal elements. This PTP was found to interact with, and dephosphorylate, Fas receptor and IkappaBalpha through the PDZ domains. This suggests it has a role in Fas mediated programmed cell death. This PTP was also shown to interact with GTPase-activating protein, and thus may function as a regulator of Rho signaling pathways. Four alternatively spliced transcript variants, which encode distinct proteins, have been reported. [provided by RefSeq, Oct 2008]

PTPN13 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.007832199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN13	NM_080683.3 linkuse as main transcript	c.744T>G	p.Asp248Glu	missense_variant	7/48	ENST00000411767.7	NP_542414.1	Q12923-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN13	ENST00000411767.7 linkuse as main transcript	c.744T>G	p.Asp248Glu	missense_variant	7/48	1	NM_080683.3	ENSP00000407249.2		Q12923-1

Frequencies

GnomAD3 genomes

AF:

0.000861

AC:

131

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000647

AC:

160

AN:

247374

Hom.:

AF XY:

0.000701

AC XY:

AN XY:

134164

show subpopulations

Gnomad AFR exome

AF:

0.000261

Gnomad AMR exome

AF:

0.000642

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000559

Gnomad SAS exome

AF:

0.0000987

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.000831

GnomAD4 exome

AF:

0.000913

AC:

1334

AN:

1460400

Hom.:

Cov.:

AF XY:

0.000885

AC XY:

643

AN XY:

726448

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000784

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.000995

GnomAD4 genome

AF:

0.000860

AC:

131

AN:

152320

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000550

AC:

ESP6500EA

AF:

0.000613

AC:

ExAC

AF:

0.000580

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.744T>G (p.D248E) alteration is located in exon 7 (coding exon 6) of the PTPN13 gene. This alteration results from a T to G substitution at nucleotide position 744, causing the aspartic acid (D) at amino acid position 248 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

.;.;.;T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.74

T;T;T;T;.

M_CAP

Benign

0.022

MetaRNN

Benign

0.0078

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;L;L;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.91

N;N;N;N;N

REVEL

Benign

0.092

Sift

Uncertain

0.015

D;D;D;D;D

Sift4G

Benign

0.47

T;T;T;T;T

Polyphen

0.96

P;D;P;D;D

Vest4

0.10

MutPred

0.20

Gain of glycosylation at T249 (P = 0.0082);Gain of glycosylation at T249 (P = 0.0082);Gain of glycosylation at T249 (P = 0.0082);Gain of glycosylation at T249 (P = 0.0082);Gain of glycosylation at T249 (P = 0.0082);

MVP

0.45

MPC

0.21

ClinPred

0.035

GERP RS

0.85

Varity_R

0.082

gMVP

0.17

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over