Genetic Variant PTPN4:p.Asp133Glu (chr2-119881816-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002830.4(PTPN4):c.399C>A(p.Asp133Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000032 in 1,563,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PTPN4
NM_002830.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41

Variant links:

Genes affected

PTPN4 (HGNC:9656): (protein tyrosine phosphatase non-receptor type 4) 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 protein contains a C-terminal PTP domain and an N-terminal domain homologous to the band 4.1 superfamily of cytoskeletal-associated proteins. This PTP has been shown to interact with glutamate receptor delta 2 and epsilon subunits, and is thought to play a role in signalling downstream of the glutamate receptors through tyrosine dephosphorylation. [provided by RefSeq, Jul 2008]

PTPN4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN4	NM_002830.4 link	c.399C>A	p.Asp133Glu	missense_variant	Exon 6 of 27	ENST00000263708.7	NP_002821.1	P29074

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PTPN4	ENST00000263708.7 link	c.399C>A	p.Asp133Glu	missense_variant	Exon 6 of 27	1	NM_002830.4	ENSP00000263708.2	P29074
PTPN4	ENST00000488279.6 link	c.420C>A	p.Asp140Glu	missense_variant	Exon 6 of 7	5		ENSP00000438445.1	F5H020
PTPN4	ENST00000433888.5 link	n.153C>A		non_coding_transcript_exon_variant	Exon 3 of 10	3		ENSP00000411364.1	J3QT89
PTPN4	ENST00000485247.1 link	n.496-316C>A		intron_variant	Intron 5 of 6	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1411430

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703542

show subpopulations

Gnomad4 AFR exome

AF:

0.0000628

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PTPN4-related disorder

Uncertain:1

Feb 02, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN4 c.399C>A variant is predicted to result in the amino acid substitution p.Asp133Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-120639392-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.2

M;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.8

D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0060

D;T

Polyphen

1.0

D;.

Vest4

0.83

MutPred

0.93

Loss of helix (P = 0.1299);.;

MVP

0.86

MPC

1.3

ClinPred

0.97

GERP RS

3.6

Varity_R

0.62

gMVP

0.72

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

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